N-aroyl cyclic amines

ABSTRACT

This invention relates to N-aroyl cyclic amine derivatives and their use as orexin antagonists  
                 
 
     wherein:  
     Y represents a bond, oxygen, or a group (CH 2 ) n , wherein n represents 1, 2 or 3;  
     m represents 1, 2, or 3; p represents ) or 1; X is NR, wherein R is H or (C 1-4 )alkyl; Ar 1  is aryl, or a mono or bicyclic heteroaryl group containing up to 3 heteroatoms selected from N, O and S; any of which may be optionally substituted; A 2  represents phenyl or a 5- or 6-membered heterocyclyl group containing up to 3 heteroatoms selected from N, O and S, wherein the phenyl or heterocyclyl group is substituted by R 1  and further optional substituents; or Ar 2  represents an optionally substituted bicyclic aromatic or bicyclic heteroaromatic group containing up to 3 heteroatoms selected from N, O and S; R 1  represents hydrogen, optionally substituted (C 1-4 )alkoxy, halo, cyano, optionally substituted (C 1-6 )alkyl, optionally substituted phenyl, or an optionally substituted 5- or 6-membered heterocyclyl group containing up to 4 heteroatoms selected from N, O and S; when Ar 1  is aryl p is not 1, or a pharmaceutical acceptable salt thereof.

[0001] This invention relates to N-aroyl cyclic amine derivatives and their use as pharmaceuticals.

[0002] Many medically significant biological processes are mediated by proteins participating in signal transduction pathways that involve G-proteins and/or second messengers.

[0003] Polypeptides and polynucleotides encoding the human 7-transmembrane G-protein coupled neuropeptide receptor, orexin-1 (HFGAN72), have been identified and are disclosed in EP-A-875565, EP-A-875566 and WO 96/34877. Polypeptides and polynucleotides encoding a second human orexin receptor, orexin-2 (HFGANP), have been identified and are disclosed in EP-A-893498.

[0004] Polypeptides and polynucleotides encoding polypeptides which are ligands for the orexin-1 receptor, e.g. orexin-A (Lig72A) are disclosed in EP-A-849361.

[0005] Orexin receptors are found in the mammalian host and may be responsible for many biological functions, including pathologies including, but not limited to, depression; anxiety, addictions; obsessive compulsive disorder; affective neurosis/disorder; depressive neurosis/disorder, anxiety neurosis; dysthymic disorder, behaviour disorder; mood disorder, sexual dysfunction; psychosexual dysfunction; sex disorder; sexual disorder; schizophrenia; manic depression; delerium; dementia; severe mental retardation and dyskinesias such as Huntington's disease and Gilles de la Tourett's syndrome; disturbed biological and circadian rhyths; feeding disorders, such as anorexia, bulimia, cachexia, and obesity; diabetes; appetite/taste disorders; vomiting/nausea; asthma; cancer; Parkinson's disease; Cushing's syndrome/disease; basophil adenoma; prolactinoma; hyperprolactinemia; hypopituitarism; hypophysis tumor/adenoma; hypothalamic diseases; Froehlich's syndrome; adrenohypophysis disease; hypophysis disease; hypophysis tumor/adenoma; pituitary growth hormone; adrenohypophysis hypofunction; adrenohypophysis hyperfunction; hypothalamic hypogonadism; Kallman's syndrome (anosmia, hyposmia); functional or psychogenic amenorrhea; hypopituitarism; hypothalamic hypothyroidism; hypothalamic-adrenal dysfunction; idiopathic hyperprolactinemia; hypothalamic disorders of growth hormone deficiency; idiopathic growth hormone deficiency; dwarfism; gigantism; acromegaly; disturbed biological and circadian rhythms; and sleep disturbances associated with such diseases as neurological disorders, neuropathic pain and restless leg syndrome, heart and lung diseases; acute and congestive heart failure; hypotension; hypertension; urinary retention; osteoporosis; angina pectoris; myocardial infarction; ischaemic or haemorrhagic stroke; subarachnoid haemorrhage; head injury such as sub-arachnoid haemorrhage associated with traumatic head injury; ulcers; allergies; benign prostatic hypertrophy; chronic renal failure; renal disease; impaired glucose tolerance; migraine; hyperalgesia; pain; enhanced or exaggerated sensitivity to pain, such as hyperalgesia, causalgia and allodynia; acute pain; burn pain; atypical facial pain; neuropathic pain; back pain; complex regional pain syndromes I and II; arthritic pain; sports injury pain; pain related to infection, e.g. HIV, post-polio syndrome, and post-herpetic neuralgia; phantom limb pain; labour pain; cancer pain; post-chemotherapy pain; post-stroke pain; post-operative pain; neuralgia; nausea and vomiting; conditions associated with visceral pain including irritable bowel syndrome, migraine and angina; urinary bladder incontinence e.g. urge incontinence; tolerance to narcotics or withdrawal from narcotics; sleep disorders; sleep apnea; narcolepsy, insomnia; parasomnia; jet-lag syndrome; and neurodegenerative disorders, which includes nosological entities such as disinhibition-dementia-parkironisin-amyotrophy complex; pallido-ponto-nigral degeneration, epilepsy, and seizure disorders.

[0006] Experiments have shown that central administration of the ligand orexin-A (described in more detail below) stimulated food intake in freely-feeding rats during a 4 hour time period. This increase was approximately four-fold over control rats receiving vehicle. These data suggest that orexin-A may be an endogenous regulator of appetite. Therefore, antagonists of its receptor may be useful in the treatment of obesity and diabetes, see Cell, 1998, 92, 573-585.

[0007] There is a significant incidence of obesity in westernised societies. According to WHO definitions a mean of 35% of subjects in 39 studies were overweight and a further 22% clinically obese. It has been estimated that 5.7% of all healthcare costs in the USA are a consequence of obesity. About 85% of Type 2 diabetics are obese, and diet and exercise are of value in all diabetics. The incidence of diagnosed diabetes in westernised countries is typically 5% and there are estimated to be an equal number undiagnosed. The incidence of both diseases is rising, demonstrating the inadequacy of current treatments which may be either ineffective or have toxicity risks including cardiovascular effects. Treatment of diabetes with sulfonylureas or insulin can cause hypoglycaernia, whilst metformin causes GI side-effects. No drug treatment for Type 2 diabetes has been shown to reduce the long-term complications of the disease. Insulin sensitisers will be useful for many diabetics, however they do not have an anti-obesity effect.

[0008] Rat sleep/EEG studies have also shown that central administration of orexin-A, an agonist of the orexin receptors, causes a dose-related increase in arousal, largely at the expense of a reduction in paradoxical sleep and slow wave sleep 2, when administered at the onset of the normal sleep period. Therefore antagonists of its receptor may be useful in the treatment of sleep disorders including insomnia.

[0009] The present invention provides N-aroyl cyclic amine derivatives which are non-peptide antagonists of human orexin receptors, in particular orexin-1 receptors. In particular, these compounds are of potential use in the treatment of obesity, including obesity observed in Type 2 (non-insulin-dependent) diabetes patients, and/or sleep disorders. Additionally these compounds are useful in the treatment of stroke, particularly ischemic or haemorrhagic stroke, and/or blocking the emetic response, i.e. useful in the treatment of nausea and vomiting.

[0010] International Patent Applications WO99/09024, WO99/58533, WO00/47577 and WO00/47580 disclose phenyl urea derivatives and WO00/47576 discloses quinolinyl cinnaide derivatives as orexin receptor antagonists. WO01/96302 discloses N-aroyl cyclic amine derivatives.

[0011] According to the invention there is provided a compound of formula (I):

[0012] wherein:

[0013] Y represents a bond, oxygen, or a group (CH₂)_(n), wherein n represents 1, 2 or 3

[0014] m represents 1, 2, or 3;

[0015] p represents 0 or 1;

[0016] X is NR, wherein R is H or (C₁₋₄)alkyl;

[0017] Ar¹ is aryl, or a mono or bicyclic heteroaryl group containing up to 3 heteroatoms selected from N, O and S; any of which may be optionally substituted;

[0018] Ar² represents phenyl or a 5- or 6-membered heterocyclyl group containing up to 3 heteroatoms selected from N, O and S, wherein the phenyl or heterocyclyl group is substituted by R¹ and further optional substituents; or Ar² represents an optionally substituted bicyclic aromatic or bicyclic heteroaromatic group containing up to 3 heteroatoms selected from N, O and S;

[0019] R¹ represents hydrogen, optionally substituted(C₁₋₄)alkoxy, halo, cyano, optionally substituted(C₁₋₆)alkyl, optionally substituted phenyl, or an optionally substituted 5- or 6-membered heterocyclyl group containing up to 4 heteroatoms selected from N, O and S;

[0020] wherein when Y is a bond Ar² can not be 2-naphthyl;

[0021] when Ar¹ is aryl p is not 1; or a pharmaceutically acceptable salt thereof.

[0022] X is preferably NH.

[0023] m is preferably 1.

[0024] p is preferably 0.

[0025] Even more preferably m is 1 when p is 0.

[0026] Preferably R is hydrogen.

[0027] Alternatively compounds of formula (I) are compounds of formula (Ia);

[0028] wherein:

[0029] Y represents a bond, oxygen, or a group (CH₂)_(n), wherein n represents 1, 2 or 3

[0030] Ar¹ is a mono or bicyclic heteroaryl group containing up to 3 heteroatoms selected from N, O and S; any of which may be optionally substituted;

[0031] Ar² represents phenyl or a 5- or 6-membered heterocyclyl group containing up to 3 heteroatoms selected from N, O and S, wherein the phenyl or heterocyclyl group is substituted by R¹ and further optional substituents; or Ar² represents an optionally substituted bicyclic aromatic or bicyclic heteroaromatic group containing up to 3 heteroatoms selected from N, O and S;

[0032] R¹ represents hydrogen, optionally substituted(C₁₋₄)alkoxy, halo, cyano, optionally substituted(C₁₋₆)alkyl, optionally substituted phenyl, or an optionally substituted 5- or 6-membered heterocyclyl group containing up to 4 heteroatoms selected from N, O and S;

[0033] wherein when Y is a bond then Ar² can not be 2-naphthyl; or pharmaceutically acceptable salts thereof.

[0034] Preferably where Ar² represents phenyl or a 5- or 6-membered heterocyclyl group containing up to 3 heteroatoms selected from N, O and S, the R¹ group is situated adjacent to the point of attachment to the amide carbonyl.

[0035] Y is preferably a bond, oxygen or (CH₂)_(n) wherein n is 1 or 2.

[0036] Even more preferably Y is a bond, oxygen or (CH₂)_(n) wherein n is 1

[0037] Alternatively R¹ represents hydrogen, optionally substituted(C₁₋₄)alkoxy, halo, optionally substituted(C₁₋₄)alkyl, optionally substituted phenyl or an optionally substituted 5- or 6-membered heterocyclyl group containing up to 3 heteroatoms selected from N, O and S.

[0038] Alternatively R¹ represents optionally substituted(C₁₋₄)alkoxy, halo, optionally substituted(C₁₋₆)alkyl, optionally substituted phenyl or an optionally substituted 5- or 6-membered heterocyclyl group containing up to 3 heteroatoms selected from N, O and S.

[0039] Preferably R¹ is selected from trifluoromethoxy, methoxy, ethoxy, halo, cyano or an optionally substituted phenyl, pyridyl, pyrazolyl, pyrimidinyl, or oxadiazolyl group.

[0040] More preferably R¹ is selected from trifluoromethoxy, methoxy, ethoxy, halo, or an optionally substituted phenyl, pyridyl, pyrazolyl, pyrimidinyl, or oxadiazolyl group.

[0041] When Ar¹ is optionally substituted aryl it is preferably phenyl. Ar¹ may have up to 5, preferably 1, 2 or 3 optional substituents.

[0042] Examples of when Ar¹ is a mono or bicyclic heteroaryl are quinoxalinyl, quinazolinyl, pyridopyrazinyl, benzoxazolyl, benzothiophenyl, benzimidazolyl, naphthyridinyl, pyridinyl, pyrimidinyl, or thiazolyl. Additionally Ar¹ can be selected from pyridazinyl, pyrazinyl, oxazolyl, triazolyl, imidazolyl, pyrazolyl, quinolinyl, benzofuranyl, indolyl, benzothiazolyl, oxazolyl[4,5-b]pyridiyl, pyridopyrimidinyl or isoquinolinyl. Furthermore Ar¹ can be furanyl or thienyl.

[0043] Preferably Ar¹ is benzoxazolyl, benzimidazolyl, quinoxalinyl, quinazolinyl, pyrimidinyl, pyridinyl, naphthyridinyl, Additionally Ar¹ can be quinolinyl, pyridopyrimidine, thiazolyl, oxazolylpyridinyl, benzothiazolyl, isoquinolinyl or pyrazinyl.

[0044] More preferably Ar¹ is benzoxazolyl, benzimidazolyl, quinoxalinyl, quinazolinyl, pyrimidinyl, pyridinyl, naphthyridinyl or oxazolyl[4,5-b]pyridinyl.

[0045] When Ar² is a 5- or 6-membered heterocyclyl group containing up to 3 heteroatoms selected from N, O and S, it may be furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, pyridyl, triazolyl, triazinyl, pyridazinyl, pyrimidinyl, isothiazolyl, isoxazolyl, pyrazinyl or pyrazolyl.

[0046] When R¹ is a 5- or 6-membered heterocyclyl group containing up to 4 heteroatoms selected from N, O and S, it may be furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, pyridyl, triazolyl, triazinyl, pyridazinyl, pyrimidinyl, isothiazolyl, isoxazolyl, pyrazinyl or pyrazolyl. Additionally it can be tetrazoyl, piperazinyl, piperidinyl, morpholinyl or thiomorpholinyl.

[0047] Preferably when R¹ is a 5- or 6-membered heterocyclic ring contaning up to 4 heteroatoms selected from N, O and S, it is furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, pyridyl, triazolyl, triazinyl, pyridazinyl, pyrimidinyl, isothiazolyl, isoxazolyl, pyrazinyl or pyrazolyl.

[0048] Preferably R¹ is a 5- or 6membered heterocyclic ring it contains up to 3 heteroatoms selected from N, O and S.

[0049] When Ar² is an optionally substituted bicyclic aromatic or bicyclic heteroaromatic it is selected from benzofuryl, benzimidazolyl, quinolinyl, quinoxalinyl or naphthyl. Additionally it may be benzotriazolyl, benzothienyl, benzoxazolyl, naphthyridinyl, isoquinolinyl or quinazolinyl. Furthermore it can be indolyl, benzothiazolyl, or benzothiadiazolyl.

[0050] Preferably Ar² represents optionally substituted phenyl, pyridyl, thiazolyl, pyrazolyl, benzofuryl, naphthyl, triazolyl, quinoxalinyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzothienyl, benzotriazolyl, benzothiazolyl, indolyl or thienyl.

[0051] Alternatively Ar² represents optionally substituted phenyl, pyridyl, thiazolyl, pyrazolyl, benzofuryl, naphthyl or triazolyl. Preferably the triazolyl is 1,2,3-triazolyl.

[0052] More preferably Ar² represents optionally substituted thiazolyl, pyrazolyl or quinolinyl.

[0053] Alternatively R¹ is selected from trifluoromethoxy, methoxy, halo, or an optionally substituted phenyl, pyridyl, pyrazolyl or oxadiazolyl group

[0054] Even more preferably R¹ represents a trifluoromethoxy group, methoxy group, iodo, or an optionally substituted phenyl, pyridyl, or oxadiazolyl group.

[0055] Optional substituents for the groups Ar¹, Ar^(2,) R and R¹ include halogen, hydroxy, oxo, cyano, nitro, (C₁₋₄)alkyl, (C₁₋₄)alkoxy, hydroxy(C₁₋₄)alkyl, hydroxy(C₁₋₄)alkoxy, halo(C₁₋₄)alkyl, halo(C₁₋₄)alkoxy, aryl(C₁₋₄)alkoxy, (C₁₋₄)alkylthio, hydroxy(C₁₋₄)alkyl, (C₁₋₄)alkoxy(C₁₋₄)alkyl, (C₃₋₆)cycloalkyl(C₁₋₄)alkoxy, (C₁₋₄)alkanoyl, (C₁₋₄)alkoxycarbonyl, (C₁₋₄)alkylsulfonyl, (C₁₋₄)alkylsulfonyloxy, (C₁₋₄)alkylsulfonyl(C₁₋₄)alkyl, arylsulfonyl, arylsulfonyloxy, arylsulfonyl(C₁₋₄)alkyl, (C₁₋₄)alkylsulfonamido, (C₁₋₄)alkylamido, (C₁₋₄)alkylsulfonamido(C₁₋₄)alkyl, (C₁₋₄)alkylamido(C₁₋₄)alkyl, arylsulfonamido, arylcarboxamido, arylsulfonamido(C₁₋₄)alkyl, arylcarboxamido(C₁₋₄)alkyl, aroyl, aroyl(C₁₋₄)alkyl, or aryl(C₁₋₄)alkanoyl group; a group R^(a)R^(b)N—, R^(a)OCO(CH₂)_(r), R^(a)CON(R^(a))(CH₂)_(r), R^(a)R^(b)NCO(CH₂)_(r), R^(a)R^(b)NSO₂(CH₂)_(r) or R^(a)SO₂NR^(b)(CH₂)_(r) where each of R^(a) and R^(b) independently represents a hydrogen atom or a (C₁₋₄)alkyl group or where appropriate R^(a)R^(b) forms part of a (C₃₋₆)azacyloalkane or (C₃₋₆)(2-oxo)azacycloalkane ring and r represents zero or an integer from 1 to 4. Additional substituents are (C₁₋₄)acyl, aryl, aryl(C₁₋₄)alkyl, (C₁₋₄)alkylamino(C₁₋₄)alkyl, R^(a)R^(b)N(CH₂)_(n)—, R^(a)R^(b)N(CH₂)_(n)O—, wherein n represents an from 1 to 4 Additionally when the substituent is R^(a)R^(b)N(CH₂)_(n)— or R^(a)R^(b)N(CH₂)_(n)O, R^(a) with at least one CH₂ of the (CH₂)_(n) portion of the group form a (C₃₋₆)azacycloalkane and R^(b) represents hydrogen, a (C₁₋₄)alkyl group or with the nitrogen to which it is attached forms a second (C₃₋₆)azacycloalkane fused to the first (C₃₋₆)azacycloalkane.

[0056] Preferred optional substituents for Ar² are halogen, cyano, (C₁₋₄)alkyl. Additional preferred optional substituents are hydroxy(C₁₋₄)alkyl, (C₁₋₄)alkoxy(C₁₋₄)alkyl, R^(a)R^(b)N(CH₂)_(n), R^(a)R^(b)N . Further optional substituents for Ar² can also be halogen, cyano, (C₁₋₄)alkyl, R^(a)R^(b)N(CH₂)_(n)O or (C₁₋₄)alkoxy.

[0057] Preferred optional substituents for Ar¹ are halogen, cyano, (C₁₋₄)alkanoyl. Other preferred substituents are hydroxy(C₁₋₄)alkyl, (C₁₋₄)alkyl or CF₃.

[0058] Preferred optional substituents for R¹ are halogen, (C₁₋₄)alkoxy(C₁₋₄)alkyl, R^(a)R^(b)N, R^(a)r^(b)N(CH₂)_(n)O and R^(a)R^(b)N(CH₂)_(n). Other preferred substituents are (C₁₋₄)alkoxy or (C₁₋₄)alkanoyl.

[0059] In the groups Ar¹ and Ar², substituents positioned ortho to one another may be linked to form a ring.

[0060] Illustrative compounds of formula (I) are selected from: Example Compound Name 1 1-[2-(Benzooxazol-2-ylaminomethyl)-piperidin-1-yl]-1-(2-methyl-5-phenyl- thiazol-4-yl)-methanone. 2 1-[2-(Benzooxazol-2-ylaminomethyl)-piperidin-1-yl]-1-biphenyl-2-yl- methanone 3 1-[2-(Benzooxazol-2-ylaminomethyl)-piperidin-1-yl]-1-[2-(3-methyl- [1,2,4]oxadiazol-5-yl)-phenyl]-methanone 4 1-[2-(Benzooxazol-2-ylaminomethyl)-piperidin-1-yl]-1-(2-trifluoromethoxy- phenyl)-methanone 5 1-[2-(Benzooxazol-2-ylaminomethyl)-piperidin-1-yl]-1-naphthalen-1-yl- methanone 6 1-[2-(Benzooxazol-2-ylaminomethyl)-piperidin-1-yl]-1-(2-methoxy-phenyl)- methanone 7 1-[2-(Benzooxazol-2-ylaminomethyl)-piperidin-1-yl]-1-(2-iodo-phenyl)- methanone 8 1-[(S)-2-(Benzooxazol-2-ylaminomethyl)-piperidin-1-yl]-1-(2-trifluoromethoxy- phenyl)-methanone 9 1-[(S)-2-(Benzooxazol-2-ylaminomethyl)-piperidin-1-yl]-1-[2-(3-methyl- [1,2,4]oxadiazol-5-yl)-phenyl]-methanone 10 1-[(S)-2-(Benzooxazol-2-ylaminomethyl)-piperidin-1-yl]-1-biphenyl-2-yl- methanone 11 1-[(S)-2-(Benzooxazol-2-ylaminomethyl)-piperidin-1-yl]-1-(2-iodo-phenyl)- methanone 12 1-[2-Benzooxazol-2-ylaminomethyl)-piperidin-1-yl]-1-phenyl-methanone 13 1-{2-[(1H-Benzoimidazol-2-ylamino)-methyl]-piperidin-1-yl}-1-[5-(4-fluoro- phenyl)-2-methyl-thiazol-4-yl]-methanone 14 1-{2-[(1H-Benzoimidazol-2-ylamino)-methyl]-piperidin-1-yl}-1-[2-(3-methyl- [1,2,4]oxadiazol-5-yl)-phenyl]-methanone 15 1-[2-(Benzothiazol-2-ylaminomethyl)-piperidin-1-yl]-1-[2-(3-methyl- [1,2,4]oxadiazol-5-yl)-phenyl]-methanone 16 1-[2-(Benzothiazol-2-ylaminomethyl)-piperidin-1-yl]-1-(2-trifluoromethoxy- phenyl)-methanone 17 1-[2-(Benzothiazol-2-ylaminomethyl)-piperidin-1-yl]-1-biphenyl-2-yl- methanone 18 1-[2-(Benzothiazol-2-ylaminomethyl)-piperidin-1-yl]-1-(2-methyl-5-phenyl- thiazol-4-yl)-methanone 19 1-[5-(4-Fluoro-phenyl)-2-methyl-thiazol-4-yl]-1-[2-(isoquinolin-1- ylaminomethyl)-piperidin-1-yl]-methanone 20 1-[2-(Isoquinolin-1-ylaminomethyl)-piperidin-1-yl]-1-[2-(3-methyl- [1,2,4]oxadiazol-5-yl)-phenyl]-methanone 21 1-[2-Isoquinolin-1-ylaminomethyl)-piperidin-1-yl]-1-(2-trifluoromethoxy- phenyl)-methanone 22 1-(2-Iodo-phenyl)-1-[2-(isoquinolin-1-ylaminomethyl)-piperidin-1-yl]- methanone 23 1-[2-(Isoquinolin-1-ylaminomethyl)-piperidin-1-yl]-1-naphthalen-1-yl- methanone 24 1-[2-(Quinoxalin-2-ylaminomethyl)-piperidin-1-yl]-1-(2-trifluoromethoxy- phenyl)-methanone 25 1-[2-(Quinoxalin-2-ylaminomethyl)-piperidin-1-yl]-1-(3-trifluoromethoxy- phenyl)-methanone 26 1-(2-Iodo-phenyl)-1-[2-(quinoxalin-2-ylaminomethyl)-piperidin-1-yl]- methanone 27 1-[5-(4-Fluoro-phenyl)-2-methyl-thiazol-4-yl]-1-[2-(quinoxalin-2- ylaminomethyl)-piperidin-1-yl]-methanone 28 1-[2-(3-Methyl-[1,2,4]oxadiazol-5-yl)-phenyl]-1-[2-(quinoxalin-2- ylaminomethyl)-piperidin-1-yl]-methanone 29 1-[5-(4-Fluoro-phenyl)-2-methyl-thiazol-4-yl]-1-[(R)-2-(quinazolin-2- ylaminomethyl)-piperidin-1-yl]-methanone 30 1-[5-(4-Fluoro-phenyl)-2-methyl-thiazol-4-yl]-1-[(S)-2-([1,5]naphthyridin-2- ylaminomethyl)-piperidin-1-yl]-methanone 31 1-[5-(4-Fluoro-phenyl)-2-methyl-thiazol-4-yl]-1-[(S)-2-([1,8]naphthyridin-2- ylaminomethyl)-piperidin-1-yl]-methanone 32 1-[(S)-2-(Benzooxazol-2-ylaminomethyl)-piperidin-1-yl]-1-[5-(4-fluoro-phenyl)- 2-methyl-thiazol-4-yl]-methanone 33 1-[3-(Benzooxazol-2-ylaminomethyl)-morpholin-4-yl]-1-[2-(3-methyl- [1,2,4]oxadiazol-5-yl)-phenyl]-methanone 34 1-[5-(4-Fluoro-phenyl)-2-methyl-thiazol-4-yl]-1-[2-(quinolin-2-ylaminomethyl)- piperidin-1-yl]-methanone 35 1-[2-(3-Methyl-[1,2,4]oxadiazol-5-yl)-phenyl]-1-[2-(quinolin-2-ylaminomethyl)- piperidin-1-yl]-methanone 36 1-[2-(Quinolin-2-ylaminomethyl)-piperidin-1-yl]-1-(2-trifluoromethoxy-phenyl)- methanone 37 1-[2-(Benzothiazol-2-ylaminomethyl)-piperidin-1-yl]-1-naphthalen-1-yl- methanone 38 1-[5-(4-Fluoro-phenyl)-2-methyl-thiazol-4-yl]-1-[(S)-2-(quinolin-2- ylaminomethyl)-piperidin-1-yl]-methanone 39 1-[5-(4-Fluoro-phenyl)-2-methyl-thiazol-4-yl]-1-[2-(pyrimidin-2- ylaminomethyl)-piperidin-1-yl]-methanone 40 1-[2-(3-Methyl-[1,2,4]oxadiazol-5-yl)-phenyl]-1-[2-(pyrimidin-2- ylaminomethyl)-piperidin-1-yl]-methanone 41 1-[5-(4-Fluoro-phenyl)-2-methyl-thiazol-4-yl]-1-[2-(pyrazin-2-ylaminomethyl)- piperidin-1-yl]-methanone 42 1-[5-(4-Fluoro-phenyl)-2-methyl-thiazol-4-yl]-1-[(S)-2-(quinazolin-4- ylaminomethyl)-piperidin-1-yl]-methanone 43 1-[5-(4-Fluoro-phenyl)-thiazol-4-yl]-1-[(S)-2-(quinazolin-4-ylaminomethyl)- piperidin-1-yl]-methanone 44 1-[4-(4-Fluoro-phenyl)-1-methyl-1H-pyrazol-3-yl]-1-[(S)-2-(quinazolin-4- ylaminomethyl)-piperidin-1-yl]-methanone 45 1-[4-(4-Fluoro-phenyl)-2-methyl-2H-pyrazol-3-yl]-1-[(S)-2-(quinazolin-4- ylaminomethyl)-piperidin-1-yl]-methanone 46 1-[4-(4-Fluoro-phenyl)-1H-pyrazol-3-yl]-1-[(S)-2-(quinazolin-4- ylaminomethyl)-piperidin-1-yl]-methanone 47 1-[5-(3-Fluoro-phenyl)-2-methyl-thiazol-4-yl]-1-[(S)-2-(quinazolin-4- ylaminomethyl)-piperidin-1-yl]-methanone 48 1-[5-(3-Fluoro-phenyl)-2-methyl-2H-[1,2,3]triazol-4-yl]-1-[(S)-2-(quinazolin-4- ylaminomethyl)-piperidin-1-yl]-methanone 49 1-Naphthalen-1-yl-1-[(S)-2-(quinazolin-4-ylaminomethyl)-piperidin-1-yl]- methanone 50 1-(5-Bromo-2-methoxy-phenyl)-1-[(S)-2-(quinazolin-4-ylaminomethyl)- piperidin-1-yl]-methanone 51 1-[2-(3-Methyl-[1,2,4]oxadiazol-5-yl)-phenyl]-1-[(S)-2-(quinazolin-4- ylaminomethyl)-piperidin-1-yl]-methanone 52 1-[(S)-2-(Quinazolin-4-ylaminomethyl)-piperidin-1-yl]-1-(2-trifluoromethoxy- phenyl)-methanone 53 1-{(S)-2-[(6,7-Difluoro-3-methyl-quinoxalin-2-ylamino)-methyl]-piperidin-1- yl}-1-[5-(4-fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanone 54 1-{(S)-2-[(6,7-Difluoro-3-methyl-quinoxalin-2-ylamino)-methyl]-piperidin-1- yl}-1-[5-(4-fluoro-phenyl)-thiazol-4-yl]-methanone 55 1-{(S)-2-[(6,7-Difluoro-3-methyl-quinoxalin-2-ylamino)-methyl]-piperidin-1- yl}-1-[4-(4-fluoro-phenyl)-1-methyl-1H-pyrazol-3-yl]-methanone 56 1-{(S)-2-[(6,7-Difluoro-3-methyl-quinoxalin-2-ylamino)-methyl]-piperidin-1- yl}-1-[4-(4-fluoro-phenyl)-1H-pyrazol-3-yl]-methanone 57 1-{(S)-2-[(6,7-Difluoro-3-methyl-quinoxalin-2-ylamino)-methyl]-piperidin-1- yl}-1-[2-(4-fluoro-phenyl)-5-methyl-2H-pyrazol-3-yl]-methanone 58 1-{(S)-2-[(6,7-Difluoro-3-methyl-quinoxalin-2-ylamino)-methyl]-piperidin-1- yl}-1-[4-(4-fluoro-phenyl)-2-methyl-2H-pyrazol-3-yl]-methanone 59 1-{(S)-2-[(6,7-Difluoro-3-methyl-quinoxalin-2-ylamino)-methyl]-piperidin-1- yl}-1-naphthalen-1-yl-methanone 60 1-{(S)-2-[(6,7-Difluoro-quinoxalin-2-ylamino)-methyl]-piperidin-1-yl}-1- quinolin-4-yl-methanone 61 1-{(S)-2-[(6,7-Difluoro-quinoxalin-2-ylamino)-methyl]-piperidin-1-yl}-1-[5-(4- fluoro-phenyl)-2-methyl-oxazol-4-yl]-methanone 62 1-{(S)-2-[(6,7-Difluoro-quinoxalin-2-ylamino)-methyl]-piperidin-1-yl}-1-[5-(4- fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanone 63 1-{(S)-2-[(6,7-Difluoro-quinoxalin-2-ylamino)-methyl]-piperidin-1-yl}-1-[2-(3- methyl-[1,2,4]oxadiazol-5-yl)-phenyl]-methanone 64 1-{(S)-2-[(6,7-Difluoro-quinoxalin-2-ylamino)-methyl]-piperidin-1-yl}-1-(2- trifluoromethoxy-phenyl)-methanone 65 1-Biphenyl-2-yl-1-{(S)-2-[(6,7-difluoro-quinoxalin-2-ylamino)-methyl]- piperidin-1-yl}-methanone 66 1-(5-Bromo-2-methoxy-phenyl)-1-{(S)-2-[(6,7-difluoro-quinoxalin-2-ylamino)- methyl]-piperidin-1-yl}-methanone 67 1-{(S)-2-[6,7-Difluoro-quinoxalin-2-ylamino)-methyl]-piperidin-1-yl}-1-[4-(4- fluoro-phenyl)-1-methyl-1H-pyrazol-3-yl]-methanone 68 1-{(S)-2-[(6,7-Difluoro-quinoxalin-2-ylamino)-methyl]-piperidin-1-yl}-1-[4-(4- fluoro-phenyl)-2-methyl-2H-pyrazol-3-yl]-methanone 69 1-{(S)-2-[(6,7-Difluoro-quinoxalin-2-ylamino)-methyl]-piperidin-1-yl}-1-[5-(4- fluoro-phenyl)-2-methyl-2H-[1,2,3]triazol-4-yl]-methanone 70 1-{(S)-2-[(6,7-Difluoro-quinoxalin-2-ylamino)-methyl]-piperidin-1-yl}-1- naphthalen-1-yl-methanone 71 1-{(S)-2-[(6,7-Difluoro-quinoxalin-2-ylamino)-methyl]-piperidin-1-yl}-1-[5-(4- fluoro-phenyl)-thiazol-4-yl]-methanone 72 1-[4-(4-Fluoro-phenyl)-1-methyl-1H-pyrazol-3-yl]-1-[(R)-2-(quinazolin-2- ylaminomethyl)-piperidin-1-yl]-methanone 73 1-[2-(3-Methyl-[1,2,4]oxadiazol-5-yl)-phenyl]-1-[2-(oxazolo[4,5-b]pyridin-2- ylaminomethyl)-piperidin-1-yl]-methanone 74 1-[2-(Oxazolo[4,5-b]pyridin-2-ylaminomethyl)-piperidin-1-yl]-1-(2- trifluoromethoxy-phenyl)-methanone 75 1-[5-(4-Fluoro-phenyl)-2-methyl-thiazol-4-yl]-1-[2-(oxazolo[4,5-b]pyridin-2- ylaminomethyl)-piperidin-1-yl]-methanone 76 1-(2-Iodo-phenyl)-1-[2-(oxazolo[4,5-b]pyridin-2-ylaminomethyl)-piperidin-1- yl]-methanone 77 1-{3-[(6,7-Difluoro-quinoxalin-2-ylamino)-methyl]-morpholin-4-yl}-1-[5-(4- fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanone 78 1-{3-[(6,7-Difluoro-quinoxalin-2-ylamino)-methyl]-morpholin-4-yl}-1-[4-(4- fluoro-phenyl)-1-methyl-1H-pyrazol-3-yl]-methanone 79 1-{3-[(6,7-Difluoro-quinoxalin-2-ylamino)-methyl]-morpholin-4-yl}-1-[4-(4- fluoro-phenyl)-2-methyl-2H-pyrazol-3-yl]-methanone 80 1-[5-(4-Fluoro-phenyl)-2-methyl-thiazol-4-yl]-1-[(S)-2-(pyrido[2,3-b]pyrazin-2- ylaminomethyl)-piperidin-1-yl]-methanone 81 1-[5-(4-Fluoro-phenyl)-2-methyl-thiazol-4-yl]-1-[(S)-2-(pyrido[2,3-b]pyrazin-3- ylaminomethyl)-piperidin-1-yl]-methanone 82 1-[5-(4-Fluoro-phenyl)-2-methyl-thiazol-4-yl]-1-{2-[(4-phenyl-thiazol-2- ylamino)-methyl]-piperidin-1-yl}-methanone 93 1-{2-[(6,7-Difluoro-quinoxalin-2-ylamino)-methyl]-pyrrolidin-1-yl}-1-[4-(4- fluoro-phenyl)-2H-pyrazol-3-yl]-methanone 94 1-{2-[(6,7-Difluoro-quinoxalin-2-ylamino)-methyl]-pyrrolidin-1-yl}-1-[5-(4- fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanone 95 1-{2-[(6,7-Difluoro-quinoxalin-2-ylamino)-methyl]-pyrrolidin-1-yl}-1-[2-(4- fluoro-phenyl)-5-methyl-2H-pyrazol-3-yl]-methanone 96 1-{2-[(6,7-Difluoro-quinoxalin-2-ylamino)-methyl]-pyrrolidin-1-yl}-1-[5-(4- fluoro-phenyl)-2-methyl-2H-[1,2,3]triazol-4-yl]-methanone 97 2-(1-{2-[(6,7-Difluoro-quinoxalin-2-ylamino)-methyl]-pyrrolidin-1-yl}- methanoyl)-benzonitrile 98 1-{2-[(6,7-Difluoro-quinoxalin-2-ylamino)-methyl]-pyrrolidin-1-yl}-1- naphthalen-1-yl-methanone 99 1-(5-Bromo-2-methoxy-phenyl)-1-{2-[(6,7-difluoro-quinoxalin-2-ylamino)- methyl]-pyrrolidin-1-yl}-methanone 100 1-{2-[(6,7-Difluoro-quinoxalin-2-ylamino)-methyl]-pyrrolidin-1-yl}-1-[2-(3- methyl-[1,2,4]oxadiazol-5-yl)-phenyl]-methanone 101 1-{(S)-2-[(6,7-Difluoro-quinoxalin-2-ylamino)-methyl]-pyrrolidin-1-yl}-1-[5-(4- fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanone 102 1-{(S)-2-[(6,7-Difluoro-quinoxalin-2-ylamino)-methyl]-pyrrolidin-1-yl}-1-[5-(4- fluoro-phenyl)-thiazol-4-yl]-methanone 103 1-{(S)-2-[(6,7-Difluoro-quinoxalin-2-ylamino)-methyl]-pyrrolidin-1-yl}-1-[2-(3- methyl-[1,2,4]oxadiazol-5-yl)-phenyl]-methanone 104 1-{(S)-2-[(6,7-Difluoro-quinoxalin-2-ylamino)-methyl]-pyrrolidin-1-yl}-1-[4-(4- fluoro-phenyl-1H-pyrazol-3-yl]-methanone 105 1-[2-(3-Methyl-[1,2,4]oxadiazol-5-yl)-phenyl]-1-[(S)-2-(oxazolo[4,5-b]pyridin- 2-ylaminomethyl)-piperidin-1-yl]-methanone 106 1-[2-(3-Methyl-[1,2,4]oxadiazol-5-yl)-phenyl]-1-{(S)-2-[(methyl-oxazolo[4,5- b]pyridin-2-yl-amino)-methyl]-piperidin-1-yl}-methanone 83 1-{(S)-2-[(6,7-Difluoro-quinoxalin-2-ylamino)-methyl]-piperidin-1-yl}-1- quinoxalin-2-yl-methanone 84 1-{(S)-2-[(6,7-Difluoro-quinoxalin-2-ylamino)-methyl]-piperidin-1-yl}-1- quinolin-3-yl-methanone 85 1-{(S)-2-[(6,7-Difluoro-quinoxalin-2-ylamino)-methyl]-piperidin-1-yl}-1- isoquinolin-3-yl-methanone 86 1-{(S)-2-[(6,7-Difluoro-quinoxalin-2-ylamino)-methyl]-piperidin-1-yl}-1-(2- methoxy-pyridin-3-yl)-methanone 87 1-{(S)-2-[(6,7-Difluoro-quinoxalin-2-ylamino)-methyl]-piperidin-1-yl}-1- quinoxalin-6-yl-methanone 88 6-[((S)-1-{1-[4-(4-Fluoro-phenyl)-1-methyl-1H-pyrazol-3-yl]-methanoyl}- piperidin-2-ylmethyl)-amino]-nicotinonitrile 89 1-[5-(4-Fluoro-phenyl)-2-methyl-thiazol-4-yl]-1-{(S)-2-[(4-trifluoromethyl- pyrimidin-2-ylamino)-methyl]-piperidin-1-yl}-methanone 90 1-(1H-Benzoimidazol-5-yl)-1-[(S)-2-(pyrido[2,3-b]pyrazin-2-ylaminomethyl)- piperidin-1-yl]-methanone Duplicate of Example 161 91 1-{(S)-2-[(6,7-Difluoro-quinoxalin-2-ylamino)-methyl]-piperidin-1-yl}-1-[2- dimethylamino-5-(4-fluoro-phenyl)-thiazol-4-yl]-methanone 92 1-{(S)-2-[(6,7-Difluoro-quinoxalin-2-ylamino)-methyl]-piperidin-1-yl}-1-[2-(3- dimethylamino-propoxy)-phenyl]-methanone 107 6-[((S)-1-{1-[4-(4-Fluoro-phenyl)-1-methyl-1H-pyrazol-3-yl]-methanoyl}- piperidin-2-ylmethyl)-methyl-amino]-nicotinonitrile 108 1-((S)-2-{[(6,7-Difluoro-quinoxalin-2-yl)-methyl-amino]-methyl}-piperidin-1- yl)-1-[4-(4-fluoro-phenyl)-1-methyl-1H-pyrazol-3-yl]-methanone

[0061] and pharmaceutically acceptable salts thereof.

[0062] Additional compounds of formula (I) are selected from: Example Compound Name 109 1-{(S)-2-[(6,7-Difluoro-quinoxalin-2-ylamino)-methyl]-piperidin-1-yl}-1-(4- fluoro-benzofuran-2-yl)-methanone 110 2-[((S)-1-{1-[5-(4-Fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanoyl}-piperidin- 2-ylmethyl)-amino]-nicotinonitrile 111 2-[((S)-1-{1-[2-(3-Methyl-[1,2,4]oxadiazol-5-yl)-phenyl]-methanoyl}-piperidin- 2-ylmethyl)-amino]-nicotinonitrile 112 2-[((S)-1-{1-[5-(4-Fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanoyl}-piperidin- 2-ylmethyl)-amino]-isonicotinonitrile 113 1-Benzo[b]thiophen-2-yl-1-{(S)-2-[(6,7-difluoro-quinoxalin-2-ylamino)- methyl]-piperidin-1-yl}-methanone 114 1-(1H-Benzoimidazol-5-yl)-1-{(S)-2-[(6,7-difluoro-quinoxalin-2-ylamino)- methyl]-piperidin-1-yl}-methanone 115 1-(1H-Benzotriazol-5-yl)-1-{(S)-2-[(6,7-difluoro-quinoxalin-2-ylamino)- methyl]-piperidin-1-yl}-methanone 116 1-Benzothiazol-6-yl-1-{(S)-2-[(6,7-difluoro-quinoxalin-2-ylamino)-methyl]- piperidin-1-yl}-methanone 117 1-(3,4-Dichloro-phenyl)-1-{(S)-2-[(6,7-difluoro-quinoxalin-2-ylamino)-methyl]- piperidin-1-yl}-methanone 118 1-{(S)-2-[(6,7-Difluoro-quinoxalin-2-ylamino)-methyl]-piperidin-1-yl}-1-(3,4- dimethoxy-phenyl)-methanone 121 1-Isoquinolin-3-yl-1-[(S)-2-(pyrido[2,3-b]pyrazin-2-ylaminomethyl)-piperidin-1- yl]-methanone 122 1-(1H-Indol-5-yl)-1-[(S)-2-(pyrido[2,3-b]pyrazin-2-ylaminomethyl)-piperidin-1- yl]-methanone 123 1-[(S)-2-(Pyrido[2,3-b]pyrazin-2-ylaminomethyl)-piperidin-1-yl]-1-quinolin-4- yl-methanone 124 1-{(S)-2-[(6,7-Difluoro-quinoxalin-2-ylamino)-methyl]-piperidin-1-yl}-1-[4-(4- fluoro-phenyl)-1-(2-methoxy-ethyl)-1H-pyrazol-3-yl]-methanone 125 1-{(S)-2-[(6,7-Difluoro-quinoxalin-2-ylamino)-methyl]-piperidin-1-yl}-1-(2,4- dimethyl-thiazol-5-yl)-methanone 126 1-{(S)-2-[(6,7-Difluoro-quinoxalin-2-ylamino)-methyl]-piperidin-1-yl}-1-[5-(4- fluoro-phenyl)-1-methyl-1H-[1,2,3]triazol-4-yl]-methanone 127 6-[((S)-1-{1-[4-(4-Fluoro-phenyl)-1-(2-methoxy-ethyl)-1H-pyrazol-3-yl]- methanoyl}-piperidin-2-ylmethyl)-amino]-nicotinonitrile 128 1-{(S)-2-[(5-Bromo-pyrimidin-2-ylamino)-methyl]-piperidin-1-yl}-1-[5-(4- fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanone 129 1-{(S)-2-[(5-Bromo-pyrimidin-2-ylamino)-methyl]-piperidin-1-yl}-1-[4-(4- fluoro-phenyl)-1H-pyrazol-3-yl]-methanone 130 1-{(S)-2-[(5-Bromo-pyrimidin-2-ylamino)-methyl]-piperidin-1-yl}-1-[5-(4- fluoro-phenyl)-2H-[1,2,3]triazol-4-yl]-methanone 131 1-{(S)-2-[(5-Bromo-pyrimidin-2-ylamino)-methyl]-piperidin-1-yl}-1-quinolin-2- yl-methanone 132 1-{(S)-2-[(5-Bromo-pyrimidin-2-ylamino)-methyl]-piperidin-1-yl}-1-[5-(4- fluoro-phenyl)-1-methyl-1H-[1,2,3]triazol-4-yl]-methanone 133 1-{(S)-2-[(5-Bromo-pyrimidin-2-ylamino)-methyl]-piperidin-1-yl}-1-[5-(4- fluoro-phenyl)-2-hydroxymethyl-thiazol-4-yl]-methanone 134 1-{(S)-2-[(5-Bromo-pyrimidin-2-ylamino)-methyl]-piperidin-1-yl}-1-[2-(3- methyl-[1,2,4]oxadiazol-5-yl)-phenyl]-methanone 135 1-{(S)-2-[(5-Bromo-pyrimidin-2-ylamino)-methyl]-piperidin-1-yl}-1-quinolin-8- yl-methanone 136 2-{[(S)-1-(1-1H-Benzoimidazol-5-yl-methanoyl)-piperidin-2-ylmethyl]-amino}- 6,7-difluoro-quinoline-3-carbonitrile 137 6,7-Difluoro-2-{[(S)-1-(1-isoquinolin-3-yl-methanoyl)-piperidin-2-ylmethyl]- amino}-quinoline-3-carbonitrile 138 6,7-Difluoro-2-[((S)-1-{1-[5-(4-fluoro-phenyl)-2-methyl-thiazol-4-yl]- methanoyl}-piperidin-2-ylmethyl)-amino]-quinoline-3-carbonitrile 139 6,7-Difluoro-2-{[(S)-1-(1-naphthalen-2-yl-methanoyl)-piperidin-2-ylmethyl]- amino}-quinoline-3-carbonitrile 140 6,7-Difluoro-2-[((S)-1-{1-[4-(4-fluoro-phenyl)-1H-pyrazol-3-yl]-methanoyl}- piperidin-2-ylmethyl)-amino]-quinoline-3-carbonitrile 141 6,7-Difluoro-2-{[(S)-1-(1-1H-indol-6-yl-methanoyl)-piperidin-2-ylmethyl]- amino}-quinoline-3-carbonitrile 142 2-{[(S)-1-(1-Benzothiazol-6-yl-methanoyl)-piperidin-2-ylmethyl]-amino}-6,7- difluoro-quinoline-3-carbonitrile 143 1-{(S)-2-[(6,7-Difluoro-quinoxalin-2-ylamino)-methyl]-piperidin-1-yl}-1- naphthalen-2-yl-methanone 144 1-{(S)-2-[(6,7-Difluoro-quinoxalin-2-ylamino)-methyl]-piperidin-1-yl)}-1-(6- fluoro-benzofuran-2-yl)-methanone 145 1-{(S)-2-[(6,7-Difluoro-quinoxalin-2-ylamino)-methyl]-piperidin-1-yl}-1-(5- fluoro-benzofuran-2-yl)-methanone 146 1-{(S)-2-[(6,7-Difluoro-quinoxalin-2-ylamino)-methyl]-piperidin-1-yl}-1-(7- fluoro-benzofuran-2-yl)-methanone 147 1-(5,7-Difluoro-benzofuran-2-yl)-1-{(S)-2-[(6,7-difluoro-quinoxalin-2-ylamino)- methyl]-piperidin-1-yl}-methanone 148 2-[((S)-1-{1-[4-(4-Fluoro-phenyl)-1H-pyrazol-3-yl]-methanoyl}-piperidin-2- ylmethyl)-amino]-nicotinonitrile 149 2-[((S)-1-{1-[4-(4-Fluoro-phenyl)-1-methyl-1H-pyrazol-3-yl]-methanoyl}- piperidin-2-ylmethyl)-amino]-nicotinonitrile 150 2-[((S)-1-{1-[4-(4-Fluoro-phenyl)-1-methyl-1H-pyrazol-3-yl]-methanoyl}- piperidin-2-ylmethyl)-amino]-isonicotinonitrile 151 1-{(S)-2-[(5-Bromo-pyrimidin-2-ylamino)-methyl]-piperidin-1-yl}-1-{2-[3-(3- dimethylamino-propoxy)-phenyl]-thiophen-3-yl}-methanone 152 1-{2-[(6,7-Difluoro-quinoxalin-2-ylamino)-methyl]-piperidin-1-yl}-1-{2-[3-(3- dimethylamino-propoxy)-phenyl]-thiophen-3-yl}-methanone 153 1-{2-[(6,7-Difluoro-quinoxalin-2-ylamino)-methyl]-piperidin-1-yl}-1-quinolin- 8-yl-methanone 154 1-{(S)-2-[(6,7-Difluoro-quinoxalin-2-ylamino)-methyl]-piperidin-1-yl)}-1-(1- methyl-1H-indol-2-yl)-methanone 155 1-{(S)-2-[(6,7-Difluoro-quinoxalin-2-ylamino)-methyl]-piperidin-1-yl}-1-(1H- indol-6-yl)-methanone 156 1-Benzo[1,2,3]thiadiazol-5-yl-1-{(S)-2-[(6,7-difluoro-quinoxalin-2-ylamino)- methyl]-piperidin-1-yl}-methanone 157 3-(1-{(S)-2-[(6,7-Difluoro-quinoxalin-2-ylamino)-methyl]-piperidin-1-yl}- methanoyl)-benzoic acid methyl ester 158 1-{(S)-2-[(6,7-Difluoro-quinoxalin-2-ylamino)-methyl]-piperidin-1-yl}-1-[1-(2- dimethylamino-ethyl)-4-(4-fluoro-phenyl)-1H-pyrazol-3-yl]-methanone 159 1-{(S)-2-[(5-Bromo-pyrimidin-2-ylamino)-methyl]-piperidin-1-yl}-1-[1-(2- dimethylamino-ethyl)-4-(4-fluoro-phenyl)-1H-pyrazol-3-yl]-methanone 160 1-[4-(4-Fluoro-phenyl)-1-(2-methoxy-ethyl)-1H-pyrazol-3-yl]-1-[(S)-2- (pyrido[2,3-b]pyrazin-2-ylaminomethyl)-piperidin-1-yl]-methanone 162 1-(1H-Benzoimidazol-5-yl)-1-{(S)-2-[(5-bromo-pyrimidin-2-ylamino)-methyl]- piperidin-1-yl}-methanone 163 1-Benzofuran-2-yl-1-{(S)-2-[(5-bromo-pyrimidin-2-ylamino)-methyl]-piperidin- 1-yl}-methanone 164 1-{(S)-2-[(5-Bromo-pyrimidin-2-ylamino)-methyl]-piperidin-1-yl}-1-(2- methoxy-phenyl)-methanone 165 1-{(S)-2-[(5-Bromo-pyrimidin-2-ylamino)-methyl]-piperidin-1-yl}-1-quinolin-4- yl-methanone 166 1-{(S)-2-[(6,7-Difluoro-quinoxalin-2-ylamino)-methyl]-piperidin-1-yl}-1-[3-(3- dimethylamino-propoxy)-phenyl]-methanone 170 1-{(S)-2-[(5-Bromo-pyrimidin-2-ylamino)-methyl]-piperidin-1-yl}-1-[4-(4- fluoro-phenyl)-1-methyl-1H-pyrazol-3-yl]-methanone 119 1-{(S)-2-[(6,7-Difluoro-quinoxalin-2-ylamino)-methyl]-pyrrolidin-1-yl}-1-[1- ethyl-4-(4-fluoro-phenyl)-1H-pyrazol-3-yl]-methanone 120 1-{(S)-2-[(6,7-Difluoro-quinoxalin-2-ylamino)-methyl]-pyrrolidin-1-yl}-1-[5-(4- fluoro-phenyl)-2H-[1,2,3]triazol-4-yl]-methanone 167 1-{(S)-2-[(5-Bromo-pyrimidin-2-ylamino)-methyl]-pyrrolidin-1-yl}-1-[4-(4- fluoro-phenyl)-1-methyl-1H-pyrazol-3-yl]-methanone 168 1-{(S)-2-[(6,7-Difluoro-quinoxalin-2-ylamino)-methyl]-pyrrolidin-1-yl}-1-[5-(2- fluoro-phenyl)-thiazol-4-yl]-methanone 169 1-{(S)-2-[(6,7-Difluoro-quinoxalin-2-ylamino)-methyl]-pyrrolidin-1-yl}-1-[4-(4- fluoro-phenyl)-1-methyl-1H-pyrazol-3-yl]-methanone 171 1-{2-[((S)-1-{1-[4-(4-Fluoro-phenyl)-1-methyl-1H-pyrazol-3-yl]-methanoyl}- piperidin-2-ylmethyl)-amino]-pyrimidin-5-yl}-ethanone 172 1-[4-(4-Fluoro-phenyl)-1-methyl-1H-pyrazol-3-yl]-1-((S)-2-{[5-(1-hydroxy- ethyl)-pyrimidin-2-ylamino]-methyl}-piperidin-1-yl)-methanone 173 2-[((S)-1-{1-[4-(4-Fluoro-phenyl)-1-methyl-1H-pyrazol-3-yl]-methanoyl}- piperidin-2-ylmethyl)-amino]-pyrimidine-5-carbonitrile 174 3-(1-{(S)-2-[(6,7-Difluoro-quinoxalin-2-ylamino)-methyl]-piperidin-1-yl}- methanoyl)-N-methyl-benzamide

[0063] and pharmaceutically acceptable salts thereof.

[0064] Further compounds of formula (I) are selected from: Example Compound Name 175 1-{(S)-2-[(5-Bromo-pyrimidin-2-ylamino)-methyl]-piperidin-1-yl}-1-phenyl- methanone 176 1-{(S)-2-[(5-Bromo-pyrimidin-2-ylamino)-methyl]-pyrrolidin-1-yl}-1-[5-(4- fluoro-phenyl)-2-hydroxymethyl-thiazol-4-yl]-methanone 177 1-{(S)-2-[(5-Bromo-pyrimidin-2-ylamino)-methyl]-pyrrolidin-1-yl}-1-[4-(4- fluoro-phenyl)-1H-pyrazol-3-yl]-methanone 178 1-{(S)-2-[(5-Bromo-pyrimidin-2-ylamino)-methyl]-pyrrolidin-1-yl}-1-quinolin-8- yl-methanone 179 1-{(S)-2-[(5-Bromo-pyrimidin-2-ylamino)-methyl]-pyrrolidin-1-yl}-1-(2-ethoxy- phenyl)-methanone 180 1-{(S)-2-[(5-Bromo-pyrimidin-2-ylamino)-methyl]-pyrrolidin-1-yl}-1-(2-methyl- 5-phenyl-thiazol-4-yl)-methanone 181 1-{(S)-2-[(5-Bromo-pyrimidin-2-ylamino)-methyl]-pyrrolidin-1-yl}-1-{5-[3-(3- dimethylamino-propoxy)-phenyl]-2-methyl-thiazol-4-yl}-methanone 182 1-{(S)-2-[(5-Bromo-pyrimidin-2-ylamino)-methyl]-pyrrolidin-1-yl}-1-(2-propoxy- phenyl)-methanone 183 1-{(S)-2-[(5-Bromo-pyrimidin-2-ylamino)-methyl]-pyrrolidin-1-yl}-1-(2- isopropoxy-phenyl)-methanone 184 1-(2-Benzyloxy-phenyl)-1-{(S)-2-[(5-bromo-pyrimidin-2-ylamino)-methyl]- pyrrolidin-1-yl}-methanone 185 1-[3-(1-{(S)-2-[(5-Bromo-pyrimidin-2-ylamino)-methyl]-pyrrolidin-1-yl}- methanoyl)-4-ethoxy-phenyl]-ethanone 186 1-{(S)-2-[(5-Bromo-pyrimidin-2-ylamino)-methyl]-pyrrolidin-1-yl}-1-(2-ethoxy- 6-methoxy-phenyl)-methanone 187 1-{(S)-2-[(5-Bromo-pyrimidin-2-ylamino)-methyl]-pyrrolidin-1-yl}-1-(2-ethoxy- 6-methyl-phenyl)-methanone 188 1-{(S)-2-[(5-Bromo-pyrimidin-2-ylamino)-methyl]-pyrrolidin-1-yl)}-1-(2-ethoxy- naphthalen-1-yl)-methanone 189 1-{(S)-2-[(5-Bromo-pyrimidin-2-ylamino)-methyl]-pyrrolidin-1-yl}-1-[5-(2- fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanone 190 1-{(S)-2-[(5-Bromo-pyrimidin-2-ylamino)-methyl]-pyrrolidin-1-yl}-1-[5-(3- fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanone 191 1-{(S)-2-[(5-Bromo-pyrimidin-2-ylamino)-methyl]-pyrrolidin-1-yl}-1-[5-(2- fluoro-phenyl)-thiazol-4-yl]-methanone 192 1-{(S)-2-[(5-Bromo-pyrimidin-2-ylamino)-methyl]-pyrrolidin-1-yl}-1-(5-phenyl- thiazol-4-yl)-methanone 193 1-{(S)-2-[(5-Bromo-pyrimidin-2-ylamino)-methyl]-pyrrolidin-1-yl}-1-(2-methyl- 4-phenyl-thiazol-5-yl)-methanone 194 1-{(S)-2-[(5-Bromo-pyrimidin-2-ylamino)-methyl]-pyrrolidin-1-yl}-1-[5-(4- fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanone 195 1-{(S)-2-[(5-Bromo-pyrimidin-2-ylamino)-methyl]-pyrrolidin-1-yl}-1-[2-(3- methyl-[1,2,4]oxadiazol-5-yl)-phenyl]-methanone 196 1-{(S)-2-[(5-Bromo-pyrimidin-2-ylamino)-methyl]-pyrrolidin-1-yl}-1-[5-(4- chloro-phenyl)-2-methyl-thiazol-4-yl]-methanone 197 1-{(S)-2-[(5-Bromo-pyridin-2-ylamino)-methyl]-pyrrolidin-1-yl}-1-[5-(4-fluoro- phenyl)-2-methyl-thiazol-4-yl]-methanone 198 1-{(S)-2-[(5-Bromo-pyridin-2-ylamino)-methyl]-pyrrolidin-1-yl}-1-[4-(4-fluoro- phenyl)-1-methyl-1H-pyrazol-3-yl]-methanone 199 1-[3-(Benzooxazol-2-ylaminomethyl)-morpholin-4-yl]-1-[2-(3-methyl- [1,2,4]oxadiazol-5-yl)-phenyl]-methanone 200 1-{3-[(5-Bromo-pyrimidin-2-ylamino)-methyl]-morpholin-4-yl}-1-[4-(4-fluoro- phenyl)-1-methyl-1H-pyrazol-3-yl]-methanone 201 1-{(S)-2-[(5-Bromo-pyrimidin-2-ylamino)-methyl]-pyrrolidin-1-yl}-1-[5-(3- fluoro-phenyl)-thiazol-4-yl]-methanone 202 1-{(S)-2-[(5-Bromo-pyrimidin-2-ylamino)-methyl]-pyrrolidin-1-yl}-1-[5-(4- methoxy-phenyl)-2-methyl-thiazol-4-yl]-methanone 203 3,5-Difluoro-4-[((S)-1-{1-[5-(4-fluoro-phenyl)-2-methyl-thiazol-4-yl]- methanoyl}-piperidin-2-ylmethyl)-amino]-benzonitrile 204 3,5-Difluoro-4-[((S)-1-{1-[4-(4-fluoro-phenyl)-1-methyl-1H-pyrazol-3-yl]- methanoyl}-piperidin-2-ylmethyl)-amino]-benzonitrile 205 3,5-Difluoro-4-[((S)-1-{1-[4-(4-fluoro-phenyl)-1H-pyrazol-3-yl]-methanoyl}- piperidin-2-ylmethyl)-amino]-benzonitrile 206 3,5-Difluoro-4-[((S)-1-{1-[2-(3-methyl-[1,2,4]oxadiazol-5-yl)-phenyl]- methanoyl}-piperidin-2-ylmethyl)-amino]-benzonitrile 207 4-{[(S)-1-(1-Benzofuran-7-yl-methanoyl)-piperidin-2-ylmethyl]-amine}-3,5- difluoro-benzonitrile 208 3,5-Difluoro-4-[((S)-1-{1-[5-(4-fluoro-phenyl)-2-methyl-thiazol-4-yl]- methanoyl}-pyrrolidin-2-ylmethyl)-amino]-benzonitrile 209 1-{(S)-2-[(5-Bromo-pyrimidin-2-ylamino)-methyl]-pyrrolidin-1-yl}-1-[2- dimethylamino-5-(4-fluoro-phenyl)-thiazol-4-yl]-methanone 210 1-(2-Amino-5-phenyl-thiazol-4-yl)-1-{(S)-2-[(5-bromo-pyrimidin-2-ylamino)- methyl]-pyrrolidin-1-yl}-methanone 211 1-{(S)-2-[(5-Bromo-pyrimidin-2-ylamino)-methyl]-pyrrolidin-1-yl}-1-[5-(3- methoxy-phenyl)-2-methyl-thiazol-4-yl]-methanone 212 1-{(S)-2-[(5-Bromo-pyrimidin-2-ylamino)-methyl]-pyrrolidin-1-yl}-1-[2-(4- fluoro-phenyl)-thiophen-3-yl]-methanone 213 1-{(S)-2-[(5-Bromo-pyrimidin-2-ylamino)-methyl]-pyrrolidin-1-yl}-1-(2-pyridin- 2-yl-phenyl)-methanone 214 1-{(S)-2-[(5-Bromo-pyrimidin-2-ylamino)-methyl]-pyrrolidin-1-yl}-1-[4-fluoro-2- (3-methyl-[1,2,4]oxadiazol-5-yl)-phenyl]-methanone 215 1-{(S)-2-[(5-Bromo-pyrimidin-2-ylamino)-methyl]-pyrrolidin-1-yl}-1-[2-(4- methoxy-phenyl)-thiophen-3-yl]-methanone 216 1-{(S)-2-[(5-Ethyl-pyrimidin-2-ylamino)-methyl]-pyrrolidin-1-yl}-1-[5-(4-fluoro- phenyl)-2-methyl-thiazol-4-yl]-methanone 217 1-((S)-2-{[(5-Bromo-pyrimidin-2-yl)-methyl-amino]-methyl}-pyrrolidin-1-yl)-1- [5-(4-fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanone 218 1-((S)-2-{[(5-Bromo-pyrimidin-2-yl)-methyl-amino]-methyl}-pyrrolidin-1-yl)-1- [4-(4-fluoro-phenyl)-1-methyl-1H-pyrazol-3-yl]-methanone 219 1-{(S)-2-[(5-Bromo-pyrimidin-2-ylamino)-methyl]-pyrrolidin-1-yl}-1-[5-(4- fluoro-phenyl)-2-methoxy-thiazol-4-yl]-methanone 220 1-{(S)-2-[(5-Bromo-pyrimidin-2-ylamino)-methyl]-pyrrolidin-1-yl}-1-[5-fluoro-2- (3-methyl-[1,2,4]oxadiazol-5-yl)-phenyl]-methanone 221 1-{(S)-2-[(5-Bromo-pyrimidin-2-ylamino)-methyl]-pyrrolidin-1-yl}-1-(2-phenyl- thiophen-3-yl)-methanone 222 2′-(1-{(S)-2-[(5-Bromo-pyrimidin-2-ylamino)methyl]-pyrrolidin-1-yl}- methanoyl)-biphenyl-4-carbonitrile 223 1-{(S)-2-[(5-Bromo-pyrimidin-2-ylamino)-methyl]-pyrrolidin-1-yl}-1-[2-(3- methoxy-phenyl)-thiophen-3-yl]-methanone 224 1-{(S)-2-[(5-Bromo-pyrimidin-2-ylamino)-methyl]-pyrrolidin-1-yl}-1-(2-pyrazol- 1-yl-phenyl)-methanone 225 1-{2-[((S)-1-{1-[5-(4-Chloro-phenyl)-2-methyl-thiazol-4-yl]-methanoyl}- pyrrolidin-2-ylmethyl)-amino]-pyrimidin-5-yl}-ethanone 226 1-{(S)-2-[(5-Chloro-pyrimidin-2-ylamino)-methyl]-pyrrolidin-1-yl}-1-[5-(4- fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanone 227 1-{(S)-2-[(5-Chloro-pyrimidin-2-ylamino)-methyl]-pyrrolidin-1-yl}-1-[2-(3- methyl-[1,2,4]oxadiazol-5-yl)-phenyl]-methanone 228 1-[5-(4-Fluoro-phenyl)-2-methyl-thiazol-4-yl]-1-{(S)-2[(5-methyl-pyrimidin-2- ylamino)-methyl]-pyrrolidin-1-yl}-methanone 229 6-[((S)-1-{1-[5-(4-Fluoro-phenyl)-2-methyl-thiazol-4-yl]methanoyl}-pyrrolidin-2- ylmethyl)-amino]-nicotinonitrile 230 5-(1-{2-[(5-Bromo-pyrimidin-2-ylamino)-methyl]-piperidin-1-yl}-methanoyl-)4H- benzo[1,4]oxazin-3-one 231 1-{(S)-2-[(5-Bromo-pyrimidin-2-ylamino)-methyl]-piperidin-1-yl}-1-[4-(4-fluoro- phenyl)-1-(2-piperidin-1-yl-ethyl)-1H-pyrazol-3-yl]-methanone 232 1-{(S)-2-[(5-Bromo-pyrimidin-2-ylamino)-methyl]-pyrrolidin-1-yl}-1-[1-(2- dimethylamino-ethyl)-4-(4-fluoro-phenyl)-1H-pyrazol-3-yl]-methanone 233 1-{(S)-2-[(5-Bromo-pyrimidin-2-ylamino)-methyl]-pyrrolidin-1-yl}-1-[2-ethyl-5- (4-fluoro-phenyl)-thiazol-4-yl]-methanone 234 1-[5-(4-Fluoro-phenyl)-2-methyl-thiazol-4-yl]-1-{(S)-2-[(6-methyl-2- methylsulfanyl-pyrimidin-4-ylamino)-methyl]-pyrrolidin-1-yl}-methanone 235 1-[5-(4-Fluoro-phenyl)-2-methyl-thiazol-4-yl]-1-{(S)-2-[(2-methylsulfanyl- pyrimidin-4-ylamino)-methyl]-pyrrolidin-1-yl}-methanone 236 1-{(S)-2-[(Dimethyl-trifluoromethyl-pyrimidin-4-ylamino)-methyl]-pyrrolidin-1- yl}-1-[5-(4-fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanone 237 1-{(S)-2-[(2,6-Dimethyl-pyrimidin-4-ylamino)-methyl]-pyrrolidin-1-yl}-1-[5-(4- fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanone 238 1-[5-(4-Fluoro-phenyl)-2-methyl-thiazol-4-yl]-1-{(S)-2-[(6-trifluoromethyl- pyrimidin-4-ylamino)-methyl]-pyrrolidin-1-yl}-methanone 239 1-(3-{[(5-Bromo-pyrimidin-2-yl)-methyl-amino]-methyl}-morpholin-4-yl)-1-[5- (4-fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanone 240 1-(3-{[(5-Bromo-pyrimidin-2-yl)-methyl-amino]-methyl}-morpholin-4-yl)-1-[2- (4-fluoro-phenyl)-thiophen-3-yl]-methanone 241 1-{(S)-2-[(5-Bromo-pyrimidin-2-ylamino)-methyl]-piperidin-1-yl}-1-(4-ethyl- quinolin-8-yl)-methanone 242 1-{(S)-2-[(5-Bromo-pyrimidin-2-ylamino)-methyl]-piperidin-1-yl}-1-isoquinolin- 1-yl-methanone 243 1-{(S)-2-[(5-Bromo-pyrimidin-2-ylamino)-methyl]-piperidin-1-yl}-1-(2-methyl- quinolin-5-yl)-methanone 244 1-{(S)-2-[(5-Bromo-pyrimidin-2-ylamino)-methyl]-piperidin-1-yl}-1-(3-methyl- quinolin-4-yl)-methanone 245 1-{(S)-2-[(5-Bromo-pyrimidin-2-ylamino)-methyl]-piperidin-1-yl}-1-(2,3- dichloro-phenyl)-methanone 246 1-{(S)-2-[(5-Bromo-pyrimidin-2-ylamino)-methyl]-piperidin-1-yl}-1-(7-chloro-3- methyl-quinolin-8-yl)-methanone 247 1-[5-(4-Chloro-phenyl)-2-methyl-thiazol-4-yl]-1-{(S)-2-[(5-chloro-pyrimidin-2- ylamino)-methyl]-pyrrolidin-1-yl}-methanone 248 1-{2-[((S)-1-{1-[2-(3-Methyl-[1,2,4]oxadiazol-5-yl)-phenyl]-methanoyl}- pyrrolidin-2-ylmethyl)-amino]-pyrimindin-5-yl}-ethanone 249 1-[5-(4-Fluoro-phenyl)-2-methyl-thiazol-4-yl]-1-{(S)-2-[(5-trifluoromethyl- pyrimidin-2-ylamino)-methyl]-pyrrolidin-1-yl}-methanone 250 1-{(S)-2-[(5-Bromo-pyrimidin-2-ylamino)-methyl]-pyrrolidin-1-yl}-1-(4-ethyl- quinolin-8-yl)-methanone 251 1-{(S)-2-[(5-Chloro-pyrimidin-2-ylamino)-methyl]-pyrrolidin-1-yl}-1-[2- dimethylamino-5-(4-fluoro-phenyl)-thiazol-4-yl]-methanone 252 1-{(S)-2-[(5-Chloro-pyrimidin-2-ylamino)-methyl]-pyrrolidin-1-yl}-1-(2-pyridin- 2-yl-phenyl)-methanone 253 1-{(S)-2-[(5-Chloro-pyrimidin-2-ylamino)-methyl]-pyrrolidin-1-yl}-1-[2-ethyl-5- (4-fluoro-phenyl)-thiazol-4-yl]-methanone 254 1-Biphenyl-2-yl-1-{(S)-2-[(5-chloro-pyrimidin-2-ylamino)-methyl]-pyrrolidin-1- yl}-methanone 255 1-{(S)-2-[(5-Bromo-pyrimidin-2-ylamino)-methyl]-pyrrolidin-1-yl}-1-(2,3- dichloro-phenyl)-methanone 256 1-{5-[3-(4-Chloro-butoxy)-phenyl]-2-methyl-thiazol-4-yl}-1-{(S)-2-[(5-chloro- pyrimidin-2-ylamino)-methyl]-pyrrolidin-1-yl}-methanone 257 1-{(S)-2-[(5-Chloro-pyrimidin-2-ylamino)-methyl]-pyrrolidin-1-yl}-1-[2-(3- isopropyl-[1,2,4]oxadiazol-5-yl}-phenyl)-methanone 258 1-{(S)-2-[(5-Bromo-pyrimidin-2-ylamino)-methyl]-pyrrolidin-1-yl}-1-[2-(3- isopropyl-[1,2,4]oxadiazol-5-yl)-phenyl]-methanone 259 1-{3-[(5-Bromo-pyridin-2-ylamino)-methyl]-morpholin-4-yl}-1-[2-(4-fluoro- phenyl)-thiophen-3-yl]-methanone 260 1-{(S)-2-[(5-Bromo-pyrimidin-2-ylamino)-methyl]-piperidin-1-yl}-1-[2,4- dimethyl-quinolin-8-yl)-methanone 261 1-{(S)-2-[(5-Bromo-pyrimidin-2-ylamino)-methyl]-piperidin-1-yl}-1-(2-phenyl- quinolin-4-yl)-methanone 262 1-{(S)-2-[(5-Bromo-pyrimidin-2-ylamino)-methyl]-piperidin-1-yl}-1-(2-methyl- quinolin-4-yl)-methanone 263 1-{(S)-2-[(5-Bromo-pyrimidin-2-ylamino)-methyl]-piperidin-1-yl}-1-(6-bromo- quinolin-4-yl)-methanone 264 1-{(S)-2-[(5-Bromo-pyrimidin-2-ylamino)-methyl]-piperidin-1-yl}-1-(2-methyl- quinolin-8-yl)-methanone 265 1-{(S)-2-[(5-Bromo-pyrimidin-2-ylamino)-methyl]-piperidin-1-yl}-1-(8-bromo- quinolin-4-yl)-methanone 266 1-{(S)-2-[(5-Bromo-pyrimidin-2-ylamino)-methyl]-piperidin-1-yl}-1-[1-(3- dimethylamino-propyl)-4-(4-fluorophenyl)-1H-pyrazol-3-yl]-methanone 267 1-{(S)-2-[(5-Chloro-pyrimidin-2-ylamino)-methyl]-piperidin-1-yl}-1-[1-(2- dimethylamino-ethyl)-4-(4-fluorophenyl)-1H-pyrazol-3-yl]-methanone 268 1-{(S)-2-[(5-Chloro-pyrimidin-2-ylamino)-methyl]-piperidin-1-yl}-1-[4-(4-fluoro- phenyl)-1-(2-piperidine-1-yl-ethyl)-1H-pyrazol-3-yl]-methanone 269 1-{(S)-2-[(5-Chloro-pyrimidin-2-ylamino)-methyl]-piperidin-1-yl}-1-[4-(4-fluoro- phenyl)-1-(3-piperidine-1-yl-propyl)-1H-pyrazol-3-yl]-methanone 270 1-((S)-2-{[(5-Bromo-pyrimidin-2-yl)-methyl-amino]-methyl}-piperidin-1-yl)-1- isoquinolin-1-yl-methanone 271 1-((S)-2-{[(5-Bromo-pyrimidin-2-yl)-methyl-amino]-methyl}-piperidin-1-yl)-1- (2,3-dichloro-phenyl)-methanone 272 1-{(S)-2-[(5-Chloro-pyrimidin-2-ylamino)-methyl]-piperidin-1-yl}-1-[2- dimethylaminomethyl-5-(4-fluoro-phenyl)-thiazol-4-yl]-methanone 273 1-((S)-2-{[(5-Bromo-pyrimidin-2-yl)-methyl-amino]-methyl}-piperidin-1-yl)-1-(3- methyl-quinolin-4-yl)-methanone 274 1-((S)-2-{[(5-Bromo-pyrimidin-2-yl)-methyl-amino]-methyl}-piperidin-1-yl)-1-(2- methyl-quinolin-5-yl)-methanone 275 1-{(S)-2-[(5-Chloro-pyrimidin-2-ylamino)-methyl]-piperidin-1-yl}-1-[5-(4-fluoro- phenyl)-2-methyl-thiazol-4-yl]-methanone

[0065] and pharmaceutically acceptable salts thereof

[0066] Preferred compounds of formula (I) are selected from: Example Compound Name 1 1-[2-(Benzooxazol-2-ylaminomethyl)-piperidin-1-yl]-1-(2-methyl-5-phenyl- thiazol-4-yl)-methanone 32 1-[(S)-2-(Benzooxazol-2-ylaminomethyl)-piperidin-1-yl]-1-[5-(4-fluoro- phenyl)-2-methyl-thiazol-4-yl]-methanone 93 1-{2-[(6,7-Difluoro-quinoxalin-2-ylamino)-methyl]-pyrrolidin-1-yl}-1-[4-(4- fluoro-phenyl)-2H-pyrazol-3-yl]-methanone 105 1-[2-(3-Methyl-[1,2,4]oxadiazol-5-yl)-phenyl]-1-[(R)-2-(oxazolo[4,5- b]pyridin-2-ylaminomethyl)-piperidin-1-yl]-methanone 106 1-[2-(3-Methyl-[1,2,4]oxadiazol-5-yl)-phenyl]-1-{(R)-2-[(methyl-oxazolo[4,5- b]pyridin-2-yl-amino)-methyl]-piperidin-1-yl}-methanone 107 6-[((S)-1-{1-[4-(4-Fluoro-phenyl)-1-methyl-1H-pyrazol-3-yl]-methanoyl}- piperidin-2-ylmethyl)-methyl-amino]-nicotinonitrile 108 1-((S)-2-{[(6,7-Difluoro-quinoxalin-2-yl)-methyl-amino]-methyl}-piperidin-1- yl)-1-[4-(4-fluoro-phenyl)-1-methyl-1H-pyrazol-3-yl]-methanone 171 1-{2-[((S)-1-{1-[4-(4-Fluoro-phenyl)-1-methyl-1H-pyrazol-3-yl]-methanoyl}- piperidin-2-ylmethyl)-amino]-pyrimidin-5-yl}-ethanone 172 1-[4-(4-Fluoro-phenyl)-1-methyl-1H-pyrazol-3-yl]-1-((S)-2-{[5-(1-hydroxy- ethyl)-pyrimidin-2-ylamino]-methyl}-piperidin-1-yl)-methanone 173 2-[((S)-1-{1-[4-(4-Fluoro-phenyl)-1-methyl-1H-pyrazol-3-yl]-methanoyl}- piperidin-2-ylmethyl)-amino]-pyrimidine-5-carbonitrile 174 3-(1-{(S)-2-[(6,7-Difluoro-quinoxalin-2-ylamino)-methyl]-piperidin-1-yl}- methanoyl)-N-methyl-benzamide 194 1-{(S)-2-[(5-Bromo-pyrimidin-2-ylamino)-methyl]-pyrrolidin-1-yl}-1-[5-(4- fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanone 195 1-{(S)-2-[(5-Bromo-pyrimidin-2-ylamino)-methyl]-pyrrolidin-1-yl}-1-[2-(3- methyl-[1,2,4]oxadiazol-5-yl)-phenyl]-methanone 196 1-{(S)-2-[(5-Bromo-pyrimidin-2-ylamino)-methyl]-pyrrolidin-1-yl}-1-[5-(4- chloro-phenyl)-2-methyl-thiazol-4-yl]-methanone 197 1-{(S)-2-[(5-Bromo-pyridin-2-ylamino)-methyl]-pyrrolidin-1-yl}-1-[5-(4- fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanone 198 1-{(S)-2-[(5-Bromo-pyridin-2-ylamino)-methyl]-pyrrolidin-1-yl}-1-[4-(4- fluoro-phenyl)-1-methyl-1H-pyrazol-3-yl]-methanone 200 1-{3-[(5-Bromo-pyrimidin-2-ylamino)-methyl]-morpholin-4-yl}-1-[4(4- fluoro-phenyl)-1-methyl-1H-pyrazol-3-yl]-methanone 203 3,5-Difluoro-4-[((S)-1-{1-[5-(4-fluoro-phenyl)-2-methyl-thiazol-4-yl]- methanoyl}-piperidin-2-ylmethyl)-amino]-benzonitrile 208 3,5-Difluoro-4-[((S)-1-{1-[5-(4-fluoro-phenyl)-2-methyl-thiazol-4-yl]- methanoyl}-pyrrolidin-2-ylmethyl)-amino]-benzonitrile 216 1-{(S)-2-[(5-Ethyl-pyrimidin-2-ylamino)-methyl]-pyrrolidin-1-yl}-1-[5-(4- fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanone 217 1-((S)-2-{[(5-Bromo-pyrimidin-2-yl)-methyl-amino]-methyl}-pyrrolidin-1-yl)- 1-[5-(4-fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanone 218 1-((S)-2-{[(5-Bromo-pyrimidin-2-yl)-methyl-amino]-methyl}-pyrrolidin-1-yl)- 1-[4-(4-fluoro-phenyl)-1-methyl-1H-pyrazol-3-yl]-methanone 225 1-{2-[((S)-1-{1-[5-(4-Chloro-phenyl)-2-methyl-thiazol-4-yl]-methanoyl}- pyrrolidin-2-ylmethyl)-amino]-pyrimidin-5-yl}-ethanone 226 1-{(S)-2-[(5-Chloro-pyrimidin-2-ylamino)-methyl]-pyrrolidin-1-yl}-1-[5-(4- fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanone 227 1-{(S)-2-[(5-Chloro-pyrimidin-2-ylamino)-methyl]-pyrrolidin-1-yl}-1-[2-(3- methyl-[1,2,4]oxadiazol-5-yl)-phenyl]-methanone 228 1-[5-(4-Fluoro-phenyl)-2-methyl-thaizol-4-yl]-1-{(S)-2-[(5-methyl-pyrimidin- 2-ylamino)-methyl]-pyrrolidin-1-yl}-methanone 229 6-[((S)-1-{1-[5-(4-Fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanyol}- pyrrolidin-2-ylmethyl)-amino]-nicotinonitrile 234 1-[5-(4-Fluoro-phenyl)-2-methyl-thiazol-4-yl]-1-{(S)-2-[(6-methyl-2- methylsulfanyl-primidin-4-ylamino)-methyl]-pyrrolidin-1-yl}-methanone 235 1-[5-(4-Fluoro-phenyl)-2-methyl-thiazol-4-yl]-1-{(S)-2-[(2-methylsulfanyl- pyrimidin-4-ylamino)-methyl]-pyrrolidin-1-yl}-methanone 239 1-(3-{[(5-Bromo-pyrimidin-2-yl)-methyl-amino]-methyl}-morpholin-4-yl)-1- [5-(4-fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanone 240 1-(3-{[(5-Bromo-pyrimidin-2-yl)-methyl-amino]-methyl}-morpholin-4-yl)-1- [2-(4-fluoro-phenyl)-thiophen-3-yl]-methanone 249 1-[5-(4-Fluoro-phenyl)-2-methyl-thiazol-4-yl]-1-{(S)-2-[(5-trifluoromethyl- pyrimidin-2-ylamino)-methyl]-pyrrolidin-1-yl}-methanone

[0067] and pharmaceutically acceptable salts thereof.

[0068] When a halogen atom is present in the compound of formula (I) it may be fluorine, chlorine, bromine or iodine.

[0069] When the compound of formula (I) contains an alkyl group, whether alone or forming part of a larger group, e.g. alkoxy or alkylthio, the alkyl group may be straight chain, branched or cyclic, or combinations thereof, it is preferably methyl or ethyl.

[0070] When used herein the term aryl means a 5- to 6 membered aromatic ring for example phenyl, or a 7 to 12 membered bicyclic ring system where at least one of the rings is aromatic for example naphthyl.

[0071] It will be appreciated that compounds of formula (I) may exist as R or S enantiomers. The present invention includes within its scope all such isomers, including mixtures. Where additional chiral centres are present in compounds of formula (I), the present invention includes within its scope all possible diostereoismers, including mixtures thereof The different isomeric forms may be separated or resolved one from the other by conventional methods, or any given isomer may be obtained by conventional synthetic methods or by stereospecific or asymmetric syntheses.

[0072] It will be understood that the invention includes pharmaceutically acceptable derivatives of compounds of formula (I) and that these are included within the scope of the invention.

[0073] Particular compounds according to the invention include those mentioned in the examples and their pharmaceutically acceptable derivatives.

[0074] As used herein “pharmaceutically acceptable derivative” includes any pharmaceutically acceptable salt, ester or salt of such ester of a compound of formula (I) which, upon administration to the recipient is capable of providing (directly or indirectly) a compound of formula (I) or an active metabolite or residue thereof.

[0075] It will be appreciated that for use in medicine the salts of the compounds of formula (I) should be pharmaceutically acceptable. Suitable pharmaceutically acceptable salts will be apparent to those skilled in the art and include acid addition salts formed with inorganic acids e.g. hydrochloric, hydrobromic, sulphuric, nitric or phosphoric acid; and organic acids e.g. succinic, maleic, acetic, fumaric, citric, tartaric, benzoic, p-toluenesulfonic, methanesulfonic or naphthalenesulfonic acid. Other salts e.g. oxalates, may be used, for example in the isolation of compounds of formula (I) and are included within the scope of this invention. Also included within the scope of the invention are solvates and hydrates of compounds of formula (I).

[0076] Certain of the compounds of formula (I) may form acid addition salts with one or more equivalents of the acid. The present invention includes within its scope all possible stoichiometric and non-stoichiometric forms.

[0077] Since the compounds of formula (I) are intended for use in pharmaceutical compositions it will readily be understood that they are each preferably provided in substantially pure form, for example at least 60% pure, more suitably at least 75% pure and preferably at least 85%, especially at least 98% pure (% are on a weight for weight basis). Impure preparations of the compounds may be used for preparing the more pure forms used in the pharmaceutical compositions.

[0078] According to a further feature of the invention there is provided a process for the preparation of compounds of formula (I) and derivatives thereof. The following schemes detail some synthetic routes to compounds of the invention.

[0079] wherein Ar¹, Ar², Y, m, p and R are as defined for formula (I), L¹ and L² are leaving groups, and P is a protecting group.

[0080] Examples of suitable leaving groups L¹ include halogen, hydroxy, OSO₂Me, OSO₂(4tolyl). The reaction of (V) with (VI) preferably proceeds in an inert solvent such as N,N-dimethylformamide in the presence of a base such as triethylamine, sodium hydride or potassium t-butoxide.

[0081] Reaction of (VIII) with (IX) proceeds in an inert solvent such as dimethylformamide or xylene in the presence of a base such as potassium carbonate or diisopropylethylamine, preferably at elevated temperatures.

[0082] Alternatively where m is 1 and p is 0 or 1 compounds maybe prepared as shown in scheme 1c.

[0083] Reaction of (XI) with an alkylating agent (C₁₋₄)L¹ proceeds in the presence of a base such as sodium hydride in an inert solvent such as dimethylformamide.

[0084] Examples of suitable leaving groups L² include halogen, hydroxy, OC(═O)alkyl and OC(═O)O-alkyl. The transformation (II) to (I) may be carried out in an inert solvent such as dichloromethane, in the presence of a base such as triethylamine. Alternatively this step may be carried out when L² represents hydroxy, in which case reaction with (II) takes place in an inert solvent such as dichloromethane in the presence of a diimide reagent such as 1-ethyl-3-(3-dimethylaminopropyl)carbodimide hydrochloride, and an activator such as 1-hydroxybenzotriazole.

[0085] Examples of protecting groups P include t-butyloxycarbonyl, trifluoroacetyl, optionally substituted benzyl and benzyloxycarbonyl. Deprotection conditions are respectively, acid (e.g. trifluoroacetic acid in dichloromethane), base (e.g. sodium hydroxide in a solvent such as aqueous methanol) and catalytic hydrogenolysis in an inert solvent (e.g using palladium on charcoal in a lower alcohol or ethyl acetate).

[0086] Compounds of formula (V), (VI) and (IX) are known in the literature or can be prepared by known methods. Compounds (VIII) can be prepared by known methods.

[0087] Within the schemes above there is scope for functional group interconversion; for example in compound (V), conversion of one value of L¹ to another value of L¹; or in compounds (IV) conversion of protecting group P for another protecting group P, or conversion of one compound of formula (I) to another of formula (I) by interconversion of substituents.

[0088] When R¹ is an aromatic group, the substituent R¹ may be introduced at the final stage as illustrated in Scheme 2 by reaction of a compound of formula (VII) where L³ represents a leaving group such as halogen (preferably bromo or iodo) or trifluoromethylsulfonyloxy, and all other variables are as previously defined, with a reagent R¹M, where M is the residue of anorganometallic species e.g. B(OH)₂ or trialkylstannyl. Such a process may be carried out in an inert solvent such as 1,2-dimethoxyethane or 1,4-dioxan, in the presence of a transition metal catalyst such as Pd(PPh₃)₄.

[0089] Wherein Y, Ar², m, p, Ar¹, R, R¹ and Y are as defined for compounds of formula (I). L³ is a leaving group.

[0090] The compounds of formula (I) may be prepared singly or as compound libraries comprising at least 2, e.g. 5 to 1000, preferably 10 to 100 compounds of formula (I). Compound libraries may be prepared by a combinatorial ‘split and mix’ approach or by multiple parallel synthesis using either solution phase or solid phase chemistry, by procedures known to those skilled in the art.

[0091] Thus according to a further aspect of the invention there is provided a compound library comprising at least 2 compounds of formula (I), or pharmaceutically acceptable derivatives thereof.

[0092] Pharmaceutically acceptable salts may be prepared conventionally by reaction with the appropriate acid or acid derivative.

[0093] The compounds of formula (I) and their pharmaceutically acceptable derivatives are useful for the treatment of diseases or disorders where an antagonist of a human Orexin receptor is required such as obesity and diabetes; prolactinoma; hypoprolactinemia; hypothalamic disorders of growth hormone deficiency, idiopathic growth hormone deficiency; Cushings syndrome/disease; hypothalamic-adrenal dysfunction; dwarfism; sleep disorders; sleep apnea; narcolepsy; insomnia; parasomnia; jet-lag syndrome; sleep disturbances associated with diseases such as neurological disorders, neuropathic pain and restless leg syndrome; heart and lung diseases; depression; anxiety; addictions; obsessive compulsive disorder; affective neurosis/disorder, depressive neurosis/disorder; anxiety neurosis; dysthymic disorder, behaviour disorder; mood disorder; sexual dysfunction; psychosexual dysfunction; sex disorder; sexual disorder; schizophrenia; manic depression; delerium; dementia; bulimia and hypopituitarism. Additionally the compounds of formula (I) and pharmaceutically acceptable derivatives are useful for the treatment of stroke, particularly ischemic or haemorrhagic and/or in blocking an emetic response i.e. nausea and vomiting.

[0094] The compounds of formula (I) and their pharmaceutically acceptable derivatives are particularly useful for the treatment of obesity, including obesity associated with Type 2 diabetes, and sleep disorders. Additionally the compounds of formula (I) and pharmaceutically acceptable derivatives are useful for the treatment of stroke, particularly ischemic or haemorrhagic and/or in blocking an emetic response i.e. nausea and vomiting.

[0095] Other diseases or disorders which may be treated in accordance with the invention include disturbed biological and circadian rhythms; adrenohypophysis disease; hypophysis disease; hypophysis tumor/adenoma; adrenohypophysis hypofunction; functional or psychogenic amenorrhea; adrenohypophysis hyperfunction; migraine; hyperalgesia; pain; enhanced or exaggerated sensitivity to pain such as hyperalgesia, causalgia and allodynia; acute pain; bum pain; atypical facial pain; neuropathic pain; back pain; complex regional pain syndromes I and II; arthritic pain; sports injury pain; pain related to infection e.g. HIV, post-polio syndrome and post-herpetic neuralgia; phantom limb pain; labour pain; cancer pain; post-chemotherapy pain; post-stroke pain; post-operative pain; neuralgia, and tolerance to narcotics or withdrawal from narcotics.

[0096] The invention also provides a method of treating or preventing diseases or disorders where an antagonist of a human Orexin receptor is required, which comprises administering to a subject in need thereof an effective amount of a compound of formula (I), or a pharmaceutically acceptable derivative thereof.

[0097] The invention also provides a compound of formula (I), or a pharmaceutically acceptable derivative thereof, for use in the treatment or prophylaxis of diseases or disorders where an antagonist of a human Orexin receptor is required.

[0098] The invention also provides the use of a compound of formula (I), or a pharmaceutically acceptable derivative thereof, in the manufacture of a medicament for the treatment or prophylaxis of diseases or disorders where an antagonist of a human Orexin receptor is required.

[0099] For use in therapy the compounds of the invention are usually administered as a pharmaceutical composition. The invention also provides a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable derivative thereof, and a pharmaceutically acceptable carrier.

[0100] The compounds of formula (I) and their pharmaceutically acceptable derivatives may be administered by any convenient method, e.g. by oral, parenteral, buccal, sublingual, nasal, rectal or transdermal administration, and the pharmaceutical-compositions adapted accordingly.

[0101] The compounds of formula (I) and their pharmaceutically acceptable derivatives which are active when given orally can be formulated as liquids or solids, e.g. as syrups, suspensions, emulsions, tablets, capsules or lozenges.

[0102] A liquid formulation will generally consist of a suspension or solution of the active ingredient in a suitable liquid carrier(s) e.g. an aqueous solvent such as water, ethanol or glycerine, or a non-aqueous solvent, such as polyethylene glycol or an oil. The formulation may also contain a suspending agent, preservative, flavouring and/or colouring agent.

[0103] A composition in the form of a tablet can be prepared using any suitable pharmaceutical carrier(s) routinely used for preparing solid formulations, such as magnesium stearate, starch, lactose, sucrose and cellulose.

[0104] A composition in the form of a capsule can be prepared using routine encapsulation procedures, e.g. pellets containing the active ingredient can be prepared using standard carriers and then filled into a hard gelatin capsule; alternatively a dispersion or suspension can be prepared using any suitable pharmaceutical carrier(s), e.g. aqueous gums, celluloses, silicates or oils and the dispersion or suspension then filled into a soft gelatin capsule.

[0105] Typical parenteral compositions consist of a solution or suspension of the active ingredient in a sterile aqueous carrier or parenterally acceptable oil, e.g. polyethylene glycol, polyvinyl pyrrolidone, lecithin, arachis oil or sesame oil. Alternatively, the solution can be lyophilised and then reconstituted with a suitable solvent just prior to administration.

[0106] Compositions for nasal administration may conveniently be formulated as aerosols, drops, gels and powders. Aerosol formulations typically comprise a solution or fine suspension of the active ingredient in a pharmaceutically acceptable aqueous or non-aqueous solvent and are usually presented in single or multidose quantities in sterile form in a sealed container which can take the form of a cartridge or refill for use with an atomising device. Alternatively the sealed container may be a disposable dispensing device such as a single dose nasal inhaler or an aerosol dispenser fitted with a metering valve. Where the dosage form comprises an aerosol dispenser, it will contain a propellant which can be a compressed gas e.g. air, or an organic propellant such as a fluorochlorohydrocarbon or hydrofluorocarbon. Aerosol dosage forms can also take the form of pump-atomisers.

[0107] Compositions suitable for buccal or sublingual administration include tablets, lozenges and pastilles where the active ingredient is formulated with a carrier such as sugar and acacia, tragacanth, or gelatin and glycerin.

[0108] Compositions for rectal administration are conveniently in the form of suppositories containing a conventional suppository base such as cocoa butter.

[0109] Compositions suitable for transdermal administration include ointments, gels and patches.

[0110] Preferably the composition is in unit dose form such as a tablet, capsule or ampoule.

[0111] The dose of the compound of formula (I), or a pharmaceutically acceptable derivative thereof, used in the treatment or prophylaxis of the abovementioned disorders or diseases will vary in the usual way with the particular disorder or disease being treated, the weight of the subject and other similar factors. However, as a general rule, suitable unit doses may be 0.05 to 1000 mg, more suitably 0.05 to 500 mg. Unit doses may be administered more than once a day for example two or three times a day, so that the total daily dosage is in the range of about 0.01 to 100 mg/kg; and such therapy may extend for a number of weeks or months. In the case of pharmaceutically acceptable derivatives the above figures are calculated as the parent compound of formula (I).

[0112] No toxicological effects are indicated/expected when a compound of formula (I) is administered in the above mentioned dosage range.

[0113] Human Orexin-A has the amino acid sequence: pyroGlu Pro Leu Pro Asp Cys Cys Arg Gln Lys Thr Cys Ser Cys Arg Leu  1              5                 10                 15 Tyr Glu Leu Leu His Gly Ala Gly Asn His Ala Ala Gly Ile Leu Thr             20                 25                 30 Leu-NH₂

[0114] Orexin-A can be employed in screening procedures for compounds which inhibit the ligand's activation of the orexin-1 receptor.

[0115] In general, such screening procedures involve providing appropriate cells which express the orexin-1 receptor on their surface. Such cells include cells from mammals, yeast, Drosophila or E. coli. In particular, a polynucleotide encoding the orexin-1 receptor is used to transfect cells to express the receptor. The expressed receptor is then contacted with a test compound and an orexin-1 receptor ligand to observe inhibition of a functional response. One such screening procedure involves the use of melanophores which are transfected to express the orexin-1 receptor, as described in WO 92/01810.

[0116] Another screening procedure involves introducing RNA encoding the orexin-1 receptor into Xenopuns oocytes to transiently express the receptor. The receptor oocytes are then contacted with a receptor ligand and a test compound, followed by detection of inhibition of a signal in the case of screening for compounds which are thought to inhibit activation of the receptor by the ligand.

[0117] Another method involves screening for compounds which inhibit activation of the receptor by determining inhibition of binding of a labelled orexin-1 receptor ligand to cells which have the receptor on their surface. This method involves transfecting a eukaryotic cell with DNA encoding the orexin-1 receptor such that the cell expresses the receptor on its surface and contacting the cell or cell membrane preparation with a compound in the presence of a labelled form of an orexin-I receptor ligand. The ligand may contain a radioactive label. The amount of labelled ligand bound to the receptors is measured, e.g. by measuring radioactivity.

[0118] Yet another screening technique involves the use of FLPR equipment for high throughput screening of test compounds that inhibit mobilisation of intracellular calcium ions, or other ions, by affecting the interaction of an orexin-1 receptor ligand with the orexin-1 receptor.

[0119] All publications, including but not limited to patents and patent applications, cited in this specification are herein incorporated by reference as if each individual publication were specifically and individually indicated to be incorporated by reference herein as though fully set forth.

[0120] The following Examples illustrate the preparation of pharmacologically active compounds of the invention. The Descriptions D1-D105 illustrate the preparation of intermediates to compounds of the invention.

[0121] In the Examples ¹H NMR's were measured at 250 MHz in CDCl₃ unless otherwise stated.

Description 1: (S) 2-Aminomethyl-piperidine-1-carboxylic acid tert butyl ester a) 2,2,2-Trifluoro-N-[(S)-1-(()-2-hydroxy-1-phenyl-ethyl)-piperidin-2-ylmethyl]-acetamide

[0122] (R)-2-[(S)-2-Aminomethyl-piperidin-1-yl]3}2-phenyl-ethanol (20.0 g) (Froelich, Olivier; Desos, Patrice; Bonin, Martine; Quirion, Jean-Charles; Husson, Henri-Philippe; Zhu, Jieping., J. Org. Chem. 1996, 61, 6700) and triethylamine (13.0 ml) were dissolved in dichloromethane (500 ml), cooled to 0° C. and trifluoroacetic anhydride (12.66 ml) added dropwise. The mixture was warmed to room temperature and stirred overnight. The organic phase was washed with water, separated, dried and solvent removed at reduced pressure. The residue was column chromatographed [silica gel, 0-10% (9:1 methanol/ammonia) in dichloromethane eluant] to give the title compound (28.0 g) as a yellow oil.

[0123] Mass Spectrum (API⁺): Found 331 (MH⁺). C₁₆H₂₁F₃N₂O₂ requires 330. [α]_(D)−55°@ 28° 1% in chloroform

b) 2,2,2-Trifluoro-N-(S)-1-piperidia-2ylmethyl-acetamide

[0124] 2,2,2-Trifluoro-N-[(S)-1-((2-hydroxy-1-phenyl-ethyl)-piperidin-2-ylmethyl]-acetamide (28.0 g) was dissolved in ethanol (200 ml) containing Pearlmans catalyst (2.0 g) and shaken under a hydrogen atmosphere (50 psi) at 50° C. for 3 hours. The reaction mixture was filtered and solvent removed at reduced pressure. The residue was column chromatographed (silica gel, 0-10% (9:1 methanol/ammonia) in dichloromethane eluant) to give the title compound (14.18 g) as a colourless oil.

[0125] Mass Spectrum (API⁺): Found 211 (MH⁺). C₈H₁₃F₃N₂O requires 210. [α]_(D)+18°@ 28° 1% in chloroform ¹H NMR δ: (d⁶-DMSO) 1.07 (1H, m), 1.32 (2H, m), 1.35-1.60 (2H, m), 1.72 (1H, m), 2.54 (1H, t), 2.70 (1H, m), 3.00 (1H, d), 3.17 (3H, m), 9.30 (1H, br. s.)

c) (S)2-[(2,2,2-Trifluoro-ethanoylamino)methyl]-piperidine-1-carboxylic acid tert butyl ester

[0126] 2,2,2-Trifluoro-N-(S)-1-piperidin-2-ylmethyl-acetamide (14.18 g) was dissolved in dichloromethane (250 ml) and treated with di-tert-butyl dicarbonate (14.95 g). The mixture was stirred for 16 h, washed with water, 2N hydrochloric acid and saturated brine, dried and solvent removed at reduced pressure to give the title compound (18.3 g)

[0127] Mass Spectrum (API⁺): Found 311 (MH⁺). C₁₃H₂₁F₃N₂O₃ requires 310. [α]_(D)−94°@ 28° 1% in chloroform ¹H NMR δ: (d⁶-DMSO) 1.27 (1H, m), 1.36, 1.47 (9H, s), 1.49-1.58 (5H, m), 2.88 (1H, m), 3.22 (1H, m), 3.49 (1H, m), 3.84 (1H, m), 4.34 (1H, m) and 9.42 (1H, br. s.).

d) (S) 2-Aminomethyl-piperidine-1-carboxylic acid tert butyl ester

[0128] (S)-2-[(2,2,2-Trifluoro-ethanoylamino)-methyl]-piperidine-1-carboxylic acid tert butyl ester (18.2 g) was dissolved in methanol (500 ml) and treated with potassium carbonate (16.1 g). After stirring for 16 h solvent was removed at reduced pressure and the residue partitioned between dichloromethane/water. The organic phase was separated, washed with brine, dried and solvent removed at reduced pressure, the residue was column chromatographed (silica gel, 0-10% (9:1 methanol/ammonia) in dichloromethane eluant) to give the title compound (8.82 g) of description 1.

[0129] Mass Spectrum (API⁺): Found 215 (MH⁺). C₁₁H₂₂N₂O₂ requires 214. [α]_(D)−32.2°@ 28° 1% in chloroform ¹H NMR δ: 1.44 (2H, m), 1.50 (9H, s), 2.64-2.80 (2H, m), 2.94 (1H, dd), 3.99 (1H, m) and 4.15 (1H, m).

Description 2: (RS) 2-(Benzoxazol-2-ylaminomethyl)-piperidine-1-carboxylic acid tert butyl ester

[0130] (RS) 2-Aminomethyl-piperidine-1-carboxylic acid tert butyl ester (0.21 g) and 2-chlorobenzoxazole (0.153 g) and triethylamine (0.1 g) were combined in tetrahydrofuran (10 ml) and stirred at room temperature for 4 hours. The mixture was partitioned between ethyl acetate and water, the organic phase dried and solvent removed at reduced pressure to give the title compound (0.36 g) as an oil that solidified on standing.

[0131] Mass Spectrum (API⁺): Found 332 (MH⁺). C₁₃H₁₇N₃O requires 331.

Description 3: (RS) Benzoxazol-2-yl-piperidin-2-ylmethyl-amine

[0132] The compound of description 2 (0.36 g) was stirred in trifluoroacetic acid (10 ml) containing water (1 drop) for 3 hours. Solvent was removed at reduced pressure and the residue column chromatographed (silica gel, 0-10% (9:1 methanol/ammonia) in dichloromethane eluant) to give the tide compound (0.23 g).

[0133] Mass Spectrum (API⁺): Found 232 (MH⁺). C₁₃H₁₇N₃O requires 231.

Description 4: (R)-2-[(S)-2-Benzooxazol-2-ylaminomethyl)-piperidin-1-yl]-2-phenyl-ethanol

[0134] A mixture of (R)-2-[(S)-2-Aminomethyl-piperidin-1-yl])2-phenyl-ethanol (1.0 g) (Froelich, Olivier; Desos, Patrice; Bonin, Martine; Quirion, Jean-Charles; Husson, Henri-Philippe; Zhu, Jieping. J. Org. Chem. 1996, 61, 6700) and 2-chlorobenzoxazole (0.66 g) were combined in tetrahydrofuran (40 ml) containing triethylamine (0.43 g) and stirred at room temperature for 1 hours. The mixture was partitioned between ethyl acetate and water, the organic phase separated, dried and solvent removed at reduced pressure, the residue was column chromatographed (silica gel, 30% pentane in ethyl acetate-ethyl acetate) to give the title compound (1.1 g). ¹H NMR δ: 1.59-1.71 (4H, m), 1.91 (1H, t), 2.73 (1H, m), 2.95 (1H, m), 3.71 (2H, m), 4.0 (1H, m), 4.10 (1H, m), 4.26 (1H, m), 5.7 (1H, m), 7.03 (1H, m), 7.17 (1H, m), 7.23-7.26 (3H, m) and 7.32-7.40 (4H, m). Mass Spectrum (API⁺): Found 352 (MH⁺). C₂₁H₂₅N₃O₂ requires 351.

Description 5: Benzoxazol-2-yl-(S)-1-piperidin-2-ylmethyl-amine

[0135] The compound of description 4 (1.15 g) in ethanol (60 ml) containing Pearlmans catalyst (0.23 g) was shaken under an atmosphere of hydrogen (50 psi) for 24 hours. Additional Pearlmans catalyst was added and shaking under hydrogen at 50 psi continued for a further 12 hours. The reaction was filtered through kiesel guhr, the filtrate evaporated at reduced pressure and the residue column chromatographed (silica gel, ethyl acetate-ethyl acetate/methanol 1:1 eluant) to give the title compound (0.49 g) as an oil. ¹H NMR δ: 1.16-1.85 (7H, m), 2.64 (1H, m), 2.85-2.99 (1H, m), 3.11 (1H, m), 3.31 (1H, m), 3.55 (1H, m), 7.00 (1H, dd), 7.12 (1H, m), 7.20 (1H, d) and 7.30 (1H, m). Mass Spectrum (API⁺): Found 232 (MH⁺). C₁₃H₁₇N₃O requires 231.

Description 6: (RS)-Benzoxazol-2-yl-(4-benzyl-morpholin-3-ylmethyl)-amine

[0136] From (4-benzyl-morphol-3-yl)-metylamine (1 g) (Morie, Toshiya; Kato, Shiro; Harada, Hiroshi; Yoshida, Naoyuki; Fujiwara, Iwao; Matsumoto, Jun-ichi., Chem. Pharm. Bull. 1995, 43, 1137-47) and 2-chlorobenzoxazole (0.78 g), the title compound (0.77 g) was prepared according to the method of D4. ¹H NMR δ: 2.33 (1H, m), 2.73-2.80 (2H, m), 3.33 (1H, d), 3.51-3.90 (6H, m), 4.10 (1H, d), 5.58 (1H, s), 7.04 (1H, m), 7.17 (1H, m) and 7.24-7.39 (7H, m).

[0137] Mass Spectrum (API⁺): Found 324 (MH⁺). C₁₉H₂₁N₃O₂ requires 323.

Description 7: (RS)-Benzoxazol-2-yl-morpholin-3-ylmethyl-amine

[0138] From the compound of D6 (0.77 g) the title compound (0.55 g) was prepared according to the method of D5. ¹H NMR δ: 2.93-3.23 (2H, m), 3.46-4.03 (7H, m), 6.95-7.23 (4H, m). Mass Spectrum (API⁺): Found 234 (MH³⁰ ) C₁₂H₁₅N₃O₂ requires 233.

Description 8: (RS) 2-(1H-Benzoimidazol-2-ylaminomethyl)-piperidine-1-carboxylic acid tert butyl ester

[0139] (RS)-2-Aminomethyl-piperidine-1-carboxylic acid tert butyl ester (0.25 g) and 2-chlorobenzimidazole (0.15 g) were combined and warmed to 100° C. for 48 hours. After cooling to room temperature the mixture was column chromatographed (silica gel, ethyl acetate/pentane 1:4-ethyl acetate/pentane 1:1 eluant) to give the title compound (0.1 g). ¹HMR δ: 1.47 (9H, m), 1.65-1.81 (7H, m), 2.85 (1H, t), 3.47 (2H, m), 3.91 (1H, d), 4.32 (1H, s), 5.78 (1H, s), 7.04 (3H, m) and 7.29 (1H, s).

[0140] Mass Spectrum (API⁺): Found 331 (MH⁺). C₁₈H₂₆N₄O₂ requires 330.

Description 9: (RS)-(1H-Benzoimidazol-2-yl)-piperidin-2-ylmethyl-amine dihydrochloride.

[0141] The compound of D8 (0.39 g) was stirred in a mixture of 4M HCl in dioxan/methanol (1:1) for 4 hours. Solvent was removed at reduced pressure to give the title compound (0.28 g) as a foam.

[0142] Mass Spectrum (API⁺): Found 231 (MH⁺). C₁₃H₁₈N₄ requires 230.

Description 10: (RS) 2-(Quinolin-2-ylaminomethyl)-piperidine-1-carboxylic acid tert butyl ester

[0143] The title compound (0.1g) was prepared from (RS) 2-aminomethyl-piperidine-1-carboxylic acid tert butyl ester (0.5 ml) and 2-chloroquinoline (0.5 g) according to the procedure of D8.

[0144] Mass Spectrum (API⁺): Found 342 (MH⁺). C₂₀H₂₇N₃O₂ requires 341.

Description 11: (RS)-Piperidin-2-ylmethyl-quinolin-2-yl-amine

[0145] The title compound (0.29 g) was prepared from the compound of D10 according to the method of D9. After removal of solvent the residue was dissolved in dichloromethane, washed with saturated sodium hydrogen carbonate, the organic phase separated, dried and solvent removed at reduced pressure to give the title compound. ¹H NMR δ: 1.20-1.96 (6H, m), 2.64 (1H, m), 2.85 (1H, m), 3.10 (1H, m), 3.35 (1H, m), 3.60 (1H, m), 5.17 (1H, m), 6.66 (1H, d), 7.19 (1H, dt), 7.48-7.58 (2H, m), 7.66 (1H, d) and 7.78 (1H, d).

[0146] Mass Spectrum (API⁺): Found 242 (MH⁺). C₁₅H₁₉N₃ requires 241.

Description 12: (RS)-2-(Benzothiazol-2-ylaminomethyl)-piperidine-1-carboxylic acid tert butyl ester

[0147] The title compound (1.2 g) after column chromatography (silica gel, 5% diethyl ether/hexane-diethyl ether eluant) was prepared from (RS) 2-aminomethyl-piperidine-1-carboxylic acid tert butyl ester (2.0 g) and 2-chlorobenzothiazole (1.58 g) according to the method of D2.

[0148] Mass Spectrum (API⁺): Found 348 (MH⁺). C₁₈H₂₅N₃O₂S requires 347.

Description 13: (RS)Benzothiazol-2-yl-piperidin-2-ylmethyl-amine

[0149] The compound of D12 (1.2 g) was dissolved in methanol (60 ml) and treated with 4N HCl in dioxan (12 ml). the mixture was stirred for 4 h, added to water containing sodium hydrogen carbonate and extracted with ethyl acetate (×3). The combined organic phase was dried and solvent removed at reduced pressure to give the title compound (0.70 g).

[0150] Mass Spectrum (API⁺): Found 348 (MH⁺). C₁₃H₁₇N₃S requires 347.

Description 14: 2-(RS)-(Isoquinolin-1-ylaminomethyl)-piperidine-1-carboxylic acid tert butyl ester

[0151] The title compound (0.76 g) was prepared from (RS) 2-aminomethyl-piperidine-1-carboxylic acid tert butyl ester (1.6 ml) and 1-chloroisoquinoline (0.8 g) according to the method used for the preparation of the compound of D8.

[0152] Mass Spectrum (API⁺): Found 342 (MH⁺). C₂₀H₂₇N₃O₂ requires 341.

Description 15: Isoquinolin-1-yl-piperidin-2-ylmethyl-amine

[0153] The title compound (0.39 g) was prepared according to the method of description 13 from the compound of D14 (0.75 g).

[0154] Mass Spectrum (API⁺): Found 242 (MH⁺). C₁₅H₁₉N₃ requires 241.

Description 16: (S) 2-Quinolin-2-ylaminomethyl)-piperidine-1-carboxylic acid tert butyl ester

[0155] The title compound (0.11 g) was prepared from (S) 2-aminomethyl-piperidine-1-carboxylic acid tert butyl ester (1.23 g) and 2-chloroquinoline (1 g) according to the procedure of D8.

[0156] Mass Spectrum (API⁺): Found 342 (MH⁺). C₂₀H₂₇N₃O₂ requires 341.

Description 17: (S)-Piperidin-2-ylmethyl-quinolin-2-yl-amine

[0157] The compound of D16 (0.11 g) was dissolved in dichloromethane (10 ml) and trifluoroacetic acid (1 ml) added. The mixture was stirred for 4 h, poured into ice containing potassium carbonate and extracted with 10% methanol/dichloromethane (×3). The combined organic extracts were dried and solvent removed at reduced pressure to give the title compound (0.05 g).

[0158] Mass Spectrum (API⁺): Found 242 (MH⁺) C₁₅H₁₉N₃ requires 241.

Description 18: (RS) 2-(Quinoxalin-2-ylaminomethyl)-piperidine-1-carboxylic acid terf butyl ester

[0159] The title compound (0.73 g) was prepared from (RS) 2-aminomethyl-piperidine-1-carboxylic acid tert butyl ester (1 ml) and 2-chloroquinoxaline (0.5 g) according to the procedure of D8.

[0160] Mass Spectrum (API⁺): Found 343 (MH⁺). C₁₉H₂₆N₄O₂ requires 342

Description 19: (RS)-Piperidin-2-ylmethyl-quinoxalin-2-yl-amine

[0161] The title compound (0.36 g) was prepared from the compound of D18 (0.71 g) according to the method of D17.

[0162] Mass Spectrum (API⁺): Found 243 (MH⁺). C₁₄H₁₈N₄ requires 242.

Description 20: (RS) 2-(Pyrimidin-2-ylaminomethyl)-piperidine-1-carboxylic acid tert butyl ester

[0163] A mixture of (RS) 2-aminomethyl-piperidine-1-carboxylic acid tert butyl ester (1.28 g) and 2-chloropyrimidine was heated at 100° C. for 48 hours. After cooling to room temperature the mixture was column chromatographed (silica gel, 0-10% (9:1 methanol/ammonia) in dichloromethane eluant) to give the title compound (0.42 g) as an oil.

[0164] Mass Spectrum (API⁺): Found 293 (MH⁺). C₁₅H₂₄N₄O₂ requires 292.

Description 21: (RS)-Piperidin-2-ylmethyl-pyrimidin-2-yl-amine

[0165] The title compound (0.350 g) was prepared from the compound of D20 (0.4 g) according to the method of D17.

[0166] Mass Spectrum (API⁺): Found 193 (MH⁺). C₁₀H₁₆N₄ requires 192.

Description 22: (RS) 2- Pyrazin-2-ylaminomethyl)-piperidine-1-carboxylic acid tert butyl ester

[0167] The title compound (0.18 g) was prepared from (RS) 2-aminomethyl-piperidine-1-carboxylic acid tert butyl ester (0.54 g) and 2-chloropyrazine according to the method of D20.

[0168] Mass Spectrum (API⁺): Found 293 (MH⁺). C₁₅H₂₄N₄O₂ requires 292.

Description 23: (RS)-Piperidin-2-ylmethyl-pyrazin-2yl-amine

[0169] The title compound (0.18 g) was prepared from the compound of D22 (0.08 g) according to the method of D17.

[0170] Mass Spectrum (API⁺): Found 193 (MH⁺). C₁₀H₁₆N₄ requires 192.

Description 24: (S)-2-(Quinazolin-4-ylaminomethyl)-piperidine-1-arboxylic acid tert butyl ester

[0171] (S)-2-Aminomethyl-piperidine-1-carboxylic acid tert-butyl ester (1.0 g), 4-chloroquinoxaline (0.768 g) and diisopropylethylamine (0.816 ml) were dissolved in tetrahydrofuran (75 ml) and heated to reflux for 6 hours under an atmosphere of argon. After cooling, the reaction solution was partitioned between ethyl acetate and water. The organic layer was washed with saturated sodium hydrogen carbonate solution, saturated brine, dried and evaporated. The residue was chromatographed over silica gel, eluting with a gradient of 50 to 100% ethyl acetate in hexane. The title compound was obtained as a white foam (1.44 g). ¹H NMR δ: 1.40 (3H, s), 2.90 (1H dt), 3.35-3.50 (1H, br.), 3.9-4.05 (1H, br.), 4.15-4.3 (1H, br.), 4.68-4.82 (1H, br.), 6.9-7.2 (1H, br.), 7.40 (1H, t), 7.65-7.85 (3H, m), 8.65(1H, s).

Description 25: (S)-2-(Quinazolin4-ylaminomethyl)-piperidine

[0172] (S)-2-(Quinazolin4-ylaminomethyl)-piperidine-1-carboxylic acid tert butyl ester (1.2 g) was dissolved in trifluoroacetic acid (60 ml) and stirred at room temperature for 2 hours. The solution was then evaporated and the residue chromatographed over silica gel, eluting with 0 to 10% (9:1 methanol-concentrated ammonia solution) in dichloromethane. The title compound was obtained as a white foam (0.84 g), MH⁺243.

Description 26: (S)-2-[(6,7-Difluoro-3-methylquinoxalin-2-ylamino)methyl]-piperidine-1-carboxylic acid tert buty ester

[0173] (S)-2-Aminomethyl-piperidine-1-carboxylic acid tert-butyl ester (1.14 g), and 2-chloro-6,7-difluoro-3-methylquinoxaline Teng et al PCT Int. Appl (2000), WO00/42026A1 20000720 (1.14 g) were dissolved in DMF (2 ml) and heated to 90° C. for 3 days under an atmosphere of argon. After cooling, the reaction solution was partitioned between ethyl acetate and water. The organic layer was washed with water, saturated brine, dried and evaporated. The residue was chromatographed over silica gel, eluting with a gradient of 10 to 50% ethyl acetate in hexane. The title compound was obtained as a pink foam (0.524 g), MH⁺393.

Description 27: (S)-2-[(6,7-Difluoro-3-methylquinoxalin-2-ylamino)methyl]-piperidine

[0174] (S)-2-[(6,7-Difluoro-3-methylquinoxalin-2-ylamino)methyl]-piperidine-1-carboxylic acid tert butyl ester (0.524 g) was dissolved in trifluoroacetic acid (15 ml) and stirred at room temperature for 3 hours. The solution was then evaporated and the residue chromatographed over silica gel, eluting with 0 to 10% (9:1 methanol-concentrated ammonia solution) in dichloromethane. The title compound was obtained as a white solid (0.289 g), MH⁺293.

Description 28: (S)-2-[(6,7-Difluoroquinoxalin-2-ylamino)methyl]-piperidine-1-carboxylic acid tert buty ester

[0175] (S)-2-Aminomethyl-piperidine-1-carboxylic acid tert-butyl ester (0.607 g), and 2-chloro-6,7-difluoroquinoxaline McQuaid et al. J. Med Chem. (1992), 35(18), 3319-24 (0.569 g) were dissolved in dimethylformamide (1 ml) and heated to 90 ° C. for 5 days under an atmosphere of argon. After cooling, the reaction solution was partitioned between ethyl acetate and water. The organic layer was washed with water, saturated brine, dried and evaporated. The residue was chromatographed over silica gel, eluting with a gradient of 10 to 50% ethyl acetate in hexane. The title compound was obtained as a pale yellow solid (0.460 g), MH⁺379.

Description 29: (S)-2-[(6,7-Difluoroquinoxalin-2-ylamino)methyl]-piperidine

[0176] (S)-2-[(6,7-Difluoroquinoxalin-2-ylamino)methyl]-piperidine-1-carboxylic acid tert butyl ester (0.460 g) was dissolved in trifluoroacetic acid (10 ml) and stirred at room temperature for 3 hours. The solution was then evaporated and the residue chromatographed over silica gel, eluting with 0 to 10% (9:1 methanol-concentrated ammonia solution) in dichloromethane. The title compound was obtained as a pale yellow foam (0.286 g), MH⁺279.

Description 30: (R,S)-2-[(6,7-Difluoro-quinoxalin-2-ylamino)-methyl]-pyrrolidine-1-carboxylic acid tert butyl ester

[0177] (R,S)-2-Aminomethyl-pyrrolidine-1-carboxylic acid tert-butyl ester. (3.0 g) and 2-chloro-6,7-difluoroquinoxaline (3.0 g) were combined in xylene (20 ml) containing diisopropylethylamine (3 ml) and heated at 130° C. for 24 hours. Solvent was removed at reduced pressure and the residue column chromatographed (silica gel, diethyl ether:petroleum ether 1:1) to give the title compound (3.4 g)

[0178] Mass Spectrum (API⁺): Found 365 (MH⁺). C₁₈H₂₂F₂N₄O₂ requires 364.

Description 31: (RS)-2-[(6,7-Difluoroquinoxalin-2-ylamino)methyl]-pyrrolidine

[0179] The compound of D30 (3.4 g) was dissolved in dichloromethane (100 ml) and treated with trifluoroacetic acid (15 ml). After 3 h additional trifluoroacetic acid (40 ml) and dichloromethane (100 ml) was added. The mixture was stirred for 48 h, poured into excess aqueous sodium hydrogen carbonate, the organic phase separated, dried and solvent removed at reduced pressure. The residue was column chromatographed (silica gel, 5% (9:1 methanol/ammonia)/dichloromethane to give the title compound (0.9 g) Mass Spectrum (API⁺): Found 265 (MH⁺). C₁₃H₁₄F₂N₄ requires 264. ¹H NMR δ: 1.56 (1H, m), 1.72-1.93 (3H, m), 2.96 (2 h, m), 3.28 (1H, m), 3.49 (1H, m), 3.64 (1H, m), 7.39 (1H, dd), 7.59 1H, dd) and 8.16 (1H, s).

Description 32: (S)-2-(quinazolin-2-ylamino)methyl-piperidine-1-carboxylic acid tert butyl ester

[0180] The title compound (0.6 g) was prepared from (S)-2-aminomethyl-piperidine-1-carboxylic acid tert-butyl ester (0.68 g) and 2-chloroquinazoline (0.53 g) according to the method of D30.

[0181] Mass Spectrum (API⁺): Found 343 (MH⁺). C₁₉H₂₆N₄O₂ requires 342.

Description 33: (S)-1-Piperidin-2-ylmethyl-quinazolin-2-yl-amine

[0182] The title compound (0.384 g) was prepared from the compound of D32 (0.6 g) according to the method of D31

[0183] Mass Spectrum (API⁺): Found 243 (MH⁺). C₁₄H₁₈N₄ requires 242. ¹H NMR δ: 1.18-1.65 6H, m), 2.66 (1H, m), 3.08-3.23 (2H, m), 3.50 (1H, m), 3.69 (1H, m), 6.16 (1h, br. s), 7.20 (1H, t), 7.54-7.69 (3H, m) and 8.91 (1H, s).

Description 34: (S)-2-([1,5]Naphthyridin-2-ylaminomethyl)-piperidine-1-carboxylic acid tert butyl ester

[0184] The title compound (0.48 g) was prepared from (S)-2-aminomethyl-piperidine-1-carboxylic acid tert-butyl ester (0.59 g) and 2-chloro-1,5-naphthyridine Rapoport, et al J. Org. Chem (1971), 36(3), 450-4 (0.40 g) according to the method of D30.

[0185] Mass Spectrum (API⁺): Found 343 (MH⁺). C₁₉H₂₆N₄O₂ requires 342.

Description 35: [1,5]Naphthyridin-2-yl-(S)-1-piperidin-2-ylmethyl-amine

[0186] The title compound (0.30 g) was prepared from the compound of D34 (0.48 g) according to the method of D31.

[0187] Mass Spectrum (API⁺): Found 243 (MH⁺). C₁₄H₁₈N₄ requires 242. ¹H NMR δ: 1.25-1.88 (6H, m), 2.68 (1H, m), 2.98 (1H, m), 3.16 (1H, m), 3.37-3.50 (1H, m), 3.66 (1H, m), 6.85 (1H, d), 7.41 1H, dd), 7.95 (1H, t) and 8.58 (1H, m).

Description 36: (S)-2-(1,8-Naphthyridin-2-ylamino)methyl-piperidine-1-carboxylic acid tert butyl ester

[0188] The title compound (0.28 g) was prepared from (S-2-aminomethyl-piperidine-1-carboxylic acid tert-butyl ester (0.35 g) and 2 chloro-1,8-naphthyridine (0.19 g) according to the method of D30.

[0189] Mass Spectrum (API⁺): Found 343 (MH⁺). C₁₉H₂₆N₄O₂ requires 342.

Description 37: [1,8]Naphthyridin-2-yl-S)-1-piperidin-2-ylmethyl-amine

[0190] The title compound (0.11 g) was prepared from the compound of D36 (0.28 g) according to the method of D31.

[0191] Mass Spectrum (API⁺): Found 243 (MH⁺). C₁₄H₁₈N₄ requires 242.

Description 38: (RS) 2-(4-Azabenzooxazol-2-ylaminomethyl-piperidine-1-carboxylic acid tert butyl ester

[0192] The title compound (0.7 g) was prepared from (RS)-2-aminomethyl-piperidine-1-carboxylic acid tert-butyl ester (0.64 g) and 2-methylthio-4-azabenzoxazole Chu-Moyeret al J. Org Chem. (1995), 60(17), 5721-S. (0.5 g) according to the method of D30.

[0193] Mass Spectrum (API⁺): Found 333 (MH⁺). C₁₇H₂₄N₄O₃ requires 332.

Description 39: (RS)-Oxazolo[4,5-b]]pyridin-2-yl-piperidin-2-ylmethyl-amine

[0194] The title compound (0.55 g) was prepared from the compound of D38 (0.7 g) according to the method of D31.

[0195] Mass Spectrum (API⁺): Found 233 (MH⁺). C₁₂H₁₆N₄O requires 232.

Description 40: ((S)-1-{1-[2-(3-Methyl-[1,2,4]-oxadiazol-5-yl)-phenyl]-methanoyl}-piperidin-2-ylmethyl)-carbamic acid tert butyl ester

[0196] A mixture of(S)-1-piperidin-2-ylmethyl-carbamic acid tert butyl ester (2.0 g) and 2-(3-methyl-[1,2,4]oxadiazol-5-yl)-benzoic acid (1.9) in dimethylformaide (10 ml containing diisopropylethylamine (2.4 ml) was treated with [O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate] (3.55 g) and stirred at 90° C. for 16 hours. Solvent was removed at reduced pressure and the residue column chromatographed (silica gel, diethyl ether eluant) to give the title compound (3.4 g).

[0197] Mass Spectrum (API⁺): Found 401 (MH⁺). C₂₁H₂₈N₄O₄ requires 400.

Description 41: 1-((S)-2-Aminomethyl-piperidin-1-yl)-1-[2-(3-methyl-[1,2,4]oxadiazol-5-yl)-phenyl)-methanone

[0198] The title compound (0.53 g) was prepared from the compound of D40 according to the method of D13.

[0199] Mass Spectrum (API⁺): Found 301 (MH⁺). C₁₆H₂₀N₄O₂requires 300.

Description 42: Methyl((S)-1-{1-[2-(3-methyl-[1,2,4]oxadiazol-5-yl)-phenyl]-methanoyl}-piperidin-2-ylmethyl)-carbamic acid dimethyl-ethyl ester

[0200] ((S)-1-{1-[2-(3-Methyl-[1,2,4]oxadiazol-5-yl)-phenyl]-methanoyl}-piperidin-2-ylmethyl)-carbamic acid tert butyl ester (0.4 g) in tetrahydrofuran (5 ml) was treated with sodium hydride (0.1 g). After evolution of hydrogen had ceased iodomethane (0.1 ml) was added and the reaction stirred for 16 hours. The reaction was quenched with ice/water, extracted with diethyl ether (×3), the combined organic extracts dried and solvent removed at reduced pressure. The residue was column chromatographed (silica gel, diethyl ether) to give the title compound (0.2 g).

[0201] Mass Spectrum (API⁺): Found 415 (MH⁺). C₂₂H₃₀N₄O₄ requires 414.

Description 43: 1-[(2-Methylaminomethyl-piperidin-1-yl])-1-[2-(3-methyl-[1,2,4]oxadiazol-5-ylphenyl]-methanone

[0202] The title compound (0.15 g) was prepared from the compound of D42 according to the method of D13.

[0203] Mass Spectrum (API⁺): Found 315 (MH⁺). C₁₁H₁₂N₄ requires 314.

Description 44: (S)-2-[(6,7-Difluoro-quinoxalin-2-ylamino)-methyl]-pyrrolidine-1-carboxylic acid tert butyl ester

[0204] The title compound (0.53 g) was prepared from (S)2-aminomethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (0.5 g) and 2-chloro-6,7-difluoroquinoxaline (0.5 g) according to the method of D30.

[0205] Mass Spectrum (API⁺): Found 365 (MH⁺). C₁₈H₂₂F₂N₄O₂ requires 364.

Description 45: (S)-2-[(6,7-Difluoroquinoxalin-2-ylamino)methyl]-pyrrolidine

[0206] The title compound (0.38 g) was prepared from the compound of D44 (0.53 g) according to the method of D31.

[0207] Mass Spectrum (API⁺): Found 265 (MH⁺). C₁₃H₁₄F₂N₄ requires 264.

Description 46: (RS)-3-[(6,7-Difluoro-quinoxalin-2-ylamino)-methyl]-morpholine-4-carboxylic acid tert butyl ester

[0208] The title compound (0.58 g) was prepared from 2-aminomethylmorpholine-4carboxylic acid tert-butyl ester (0.82 g) and 2-chloro-6,7-difluoroquinoxaline (0.76 g) according to the method of D30.

[0209] Mass Spectrum (API⁺): Found 381 (MH⁺). C₁₈H₂₂F₂N₄O₃ requires 380.

Description 47: (6,7-Difluoro-quinoxalin-2-yl)-morpholin-3-ylmethyl-amine

[0210] The compound of D46 (0.58 g) was dissolved in trifluoroacetic acid and stirred for 3 hours. Solvent was removed at reduced pressure and the residue partitioned between aqueous sodium hydrogen carbonate and ethyl acetate. The organic phase was separated dried, solvent removed at reduced pressure and the residue column chromatographed ( silica gel, 0-10% (9:1 methanol/ammonia) in dichloromethane, eluant ) to give the title compound (0.327 g).

[0211] Mass Spectrum (API⁺): Found 281 (MH⁺). C₁₃H₁₄F₂N₄O requires 280.

Description 48: 2-(Pyrido[2,3-b]pyrazin-2-ylaminomethyl)-piperidine-1-carboxylic acid tert butyl ester and 2-(Pyrido[2,3-b]-pyrazin-3-ylaminomethyl)-piperidine-1-carboxylic acid tert butyl ester

[0212] A mixture of(S)-2-aminomethyl-piperidine-1-carboxylic acid tert butyl ester (1.0 g) and a 2:1 mixture of 2-chloro-pyrido[2,3-b]pyraine and 3-chloro-pyrido[2,3-b]pyrazine (0.8 g) was combined and warmed to 90° C. for 18 hours. The mixture was diluted with ethyl acetate, washed with aqueous sodium hydrogen carbonate and water, the organic phase dried and solvent was removed at reduced pressure. The residue was column chromatographed (silica gel, dichloromethane 0 to 6% ethanol in dichloromethane, 1% increments) to give as the faster running component 2-(pyrido[2,3-b]pyrazin-2-ylaminomethyl)-piperidine-1-carboxylic acid tert butyl ester (0.48 g). mass spectrum (API⁺): Found 344 (MH⁺). C₁₇H₂₅N₅O2 requires 343 and 2-(pyrido[2,3-b]pyrazin-3-ylaminomethyl)-piperidine-1-carboxylic acid tert butyl ester (0.3 g) mass spectrum (API⁺): Found 344 (MH⁺). C₁₇H₂₅N₅O2 requires 343.

Description 49: Piperidin-2-ylmethyl-pyrido[2,3-b]pyrazin-2-yl-amine trifluoroacetate salt

[0213] 2 (Pyrido[2,3-b]pyrazin-2-ylaminomethyl)-piperidine-1-carboxylic acid tert butyl ester (0.48 g) was dissolved in dichloromethane (3 ml), cooled (ice bath) and treated with trifluoroacetic acid (2 ml). The mixture was stirred for 3 hours at room temperature, solvent removed at reduced pressure and the residue co-evaporated with toluene to give the title compound (0.45 g).

[0214] Mass spectrum (API⁺): Found 244 (MH⁺). C₁₃H₁₇N₅ requires 243.

Description 50: Piperidin-2-ylmethyl-pyrido[2,3-b]pyrazin-3yl-amine trifluoroacetate salt

[0215] The title compound (0.3 g) was prepared from 2-pyrido[2,3-b]pyrazin-3-ylaminomethyl)-piperidine-1-carboxylic acid tert butyl ester (0.3 g) according to the method of description 49

[0216] Mass spectrum (API⁺): Found 244 (MH⁺). C₁₃H₁₇N₅ requires 243.

Description 51: 2-Thioureidomethyl-piperidine-1-carboxylic acid tert butyl ester

[0217] Benzoyl chloride (1.2 ml) was added dropwise to sodium thiocyanate (0.90 g) in acetone (50 ml). When the addition was complete the mixture was refluxed for 15 minutes, cooled to room temperature and (RS) 2-aminomethyl-piperidine-1-carboxylic acid tert butyl ester (2.0 g) in acetone (5 ml) added. The mixture was refluxed for 2 hours, cooled to room temperature and solvent removed at reduced pressure. The residue was column chromatographed (silica gel, 0-10% (9:1 methanol/ammonia) in dichloromethane eluant) to give the title product (1.95 g).

[0218] Mass spectrum (API⁺): Found 274 (MH⁺). C₁₂H₂₃N₃O₂S requires 273.

Description 52: 2-[(4-Phenyl-thiazol-2-ylamino)-methyl)-piperidine-1-carboxylic acid pert butyl ester

[0219] The compound of description 51 (1.95 g) was dissolved in ethanol (100 ml) containing triethylamine (0.99 ml). Phenacyl bromide (1.42 g) was added and the mixture stirred for 16 hours. Solvent was removed at reduced pressure and the residue partitioned between ethyl acetate and water. The organic phase was separated and solvent removed at reduced pressure. The residue was column chromatographed (silica gel, dichloromethane eluant) to give the title compound (2.42 g).

[0220] Mass spectrum (API⁺): Found 274 (MH⁺). C₂₀H₂₇N₃O₂S requires 273.

Description 53: (4Phenyl-thiazol-2-yl-piperidin-2-ylmethyl-amine

[0221] The tide compound (1.55 g) was prepared from the compound of D52 (2.42 g) according to the method of D47.

[0222] Mass spectrum (API⁺): Found 174 (MH⁺). C₁₅H₁₉N₃O₂S requires 173.

Description 54: 2-[(5-Cyano-pyridin-2-ylamino)methyl]-piperidine-1-carboxylic acid tert butyl ester.

[0223] The title compound (1.54 g) was prepared from (S)-2-aminomethyl-piperidine-1-carboxylic acid tert-butyl ester (2.0 g) and 2-chloro-5-cyanopyridine (1.29 g) in the presence of diisopropylethylamine (1.21 g) according to the method of D28.

[0224] Mass spectrum (API⁺): Found 317 (MH⁺). C₁₇H₂₄N₄O₂ requires 316.

Description 55: 6-[(Piperidin-2-ylmethyl)-amino]-nicotinonitrile

[0225] The title compound (1.56 g) was prepared from the compound of D54 (1.53 g) and tifluoroacetic acid according to the method of D29.

[0226] Mass spectrum (API⁺): Found 217 (MH⁺). C₁₂H₁₆N₄ requires 216.

Description 56: 2-[(4-Trifluoromethyl-pyrimidin-2-ylamino)methyl]-piperidine-1-carboxylic acid tert butyl ester

[0227] The title compound (0.298 g) was prepared from (S)-2-aminomethyl-piperidine-1-carboxylic acid tert-butyl ester (1.0 g) and 2-chloro-4-trifluoropyrimidine (0.85 g) according to the method of D28.

[0228] Mass spectrum (API⁺): Found 361 (MH⁺). C₁₆H₂₃F₃N₄O₂ requires 360.

Description 57: Piperidin-2-ylmethyl-(4-trifluoromethyl-pyrimidin-2-yl)-amine.

[0229] The title compound (0.25 g) was prepared from the compound of D56 (0.29 g) and trifluoroacetic acid according to the method of D29.

[0230] Mass spectrum (API⁺): Found 261 (MH⁺). C₁₁H₁₅F₃N₄ requires 260.

Description 58: ((S)-1-{1-[4-(4-Fluoro-phenyl)-1-methyl-1H-pyrazol-3-yl]-methanoyl}-piperidin-2-ylmethyl)-carbamic acid pert butyl ester

[0231] The title compound (3.96 g) was prepared from (S)-1-piperidin-2-ylmethyl-carbamic acid tert butyl ester (2.14 g) and 4-(4-fluoro-phenyl)-1-methyl-1H-pyrazol-3-yl carboxylic acid (2.20 g) according to the method of D40.

[0232] Mass spectrum (API⁺): Found 417 (MH⁺). C₂₂H₂₉FN₄O₃ requires 416.

Description 59: ((S)-1-{1-[4-(4-Fluoro-phenyl)-1-methyl-1H-pyrazol-3-yl]-methanoyl}-piperidin-2-ylmethyl)-methyl-carbamic acid dimethyl-ethyl ester.

[0233] The title compound (2.0 g) was prepared from the compound of description 58 (3.85 g) according to the method of D42.

[0234] Mass spectrum (API⁺): Found 431 (MH⁺). C₂₃H₃₁FN₄O₃ requires 430

Description 60: 1-[4-(4-Fluoro-phenyl)-1-methyl-1H-pyrazol-3-yl]-1-((S)-2-methylaminomethyl-piperidin-1-yl)methanone

[0235] The title compound (0.5 g) was prepared for the compound of D59 (0.50 g) according to the method of D29.

Description 61: (S)-2-[(3Cyano-pyridin-2-ylamino)methyl]-piperidine-1-carboxylic acid tert butyl ester

[0236] The title compound (0.66 g) was prepared from (S)-2-aminomethyl-piperidine-1-carboxylic acid tert-butyl ester (1.55 g) and 2-chloro-3-cyanopyridine (1.0 g) according to the method of D28.

[0237] Mass spectrum (API⁺): Found 317 (MH⁺). C₁₇H₂₄N₄O₂ requires 316

Description 62: 2-[((S)-1-Piperidin-2-ylmethyl)-amino]-nicotinonitrile

[0238] The title compound (0.53 g) was prepared from the compound of D61 (0.663 g) and trifluoroacetic acid according to the method of D29.

[0239] Mass spectrum (API⁺): Found 217 (MH⁺). C₁₂H₁₆N₄ requires 216

Description 63: (S)-2-[(4-Cyano-pyridin-2-ylamino)-methyl]-piperidine-1-carboxylic acid tert butyl ester

[0240] The title compound (0.24 g) was prepared from (S)-2-aminomethyl-piperidine-1-carboxylic acid tert-butyl ester (1.14 g) and 2-chloro-4-cyanopyridine (0.74 g) according to the method of D28.

[0241] Mass spectrum (API⁺): Found 317 (MH⁺). C₁₇H₂₄N₄O₂ requires 316

Description 64: 4-Cyano-2-[((S)-1-Piperidin-2-ylmethyl)-amino]-pyridine

[0242] The title compound (0.17 g) was prepared from the compound of D63 (0.243 g) and trifluoroacetic acid according to the method of D29.

[0243] Mass spectrum (API⁺): Found 217 (MH⁺). C₁₂H₁₆N₄ requires 216

Description 65: (S)2-[(5-Bromo-pyrimidin-2-ylamino)-methyl]-piperidine-1-carboxylic acid tert butyl carbonate.

[0244] (S)-2-Aminomethyl-piperidine-1-carboxylic acid tert butyl ester (1 g), 5-bromo-2-chloropyrimidine (0.9 g) were combined in xylene (20 ml) containing potassium carbonate (1.29 g) and diisopropylethylamine (2.43 g) and warmed to reflux for 48 h. The mixture was cooled to room temperature, filtered and solvent removed at reduced pressure. The residue was column chromatographed (silica gel, pentane—25% ethyl acetate/pentane). The appropriate fractions were collected, solvent removed at reduced pressure to give the title compound (1.43 g) as a colourless gum

[0245] Mass spectrum (API⁺): Found 272 (MH⁺). C₁₀H₁₄N₄Br requires 371

Description 66: (S) (5-Bromo-pyrimidin-2-yl)-piperidin-2-ylmethyl-amine

[0246] The title compound (1.40 g) was prepared from the compound of D65 (2.1 g) according to the method of D9.

[0247] Mass spectrum (API⁺): Found 272 (MH⁺). C₁₀H₁₄N₄Br requires 271.

Description 67: (S) 2-[(3-Cyano-6,7-difluoro-quinolin-2-ylamino)-methyl]-piperidine-1-carboxylic acid tert butyl ester.

[0248] (S)2-Aminomethyl-piperidine-1-carboxylic acid tert-butyl ester (1.1 g) and 2-chloro-3-cyano-5,6difluoroquinoline (1.12 g) according to the method of D28 were combined in xylene (15 ml) containing potassium carbonate (4.0 g) and diisopropylethylamine (4 ml) and boiled for 20 hours. The reaction mixture was cooled to room temperature, filtered and solvent removed at reduced pressure. The residue was column chromatographed (silica gel, dichloromethane eluant) to give after combining appropriate fractions the title compound (1.8 g).

[0249] Mass spectrum (API⁺): Found 403 (MH⁺). C₂₁H₂₄F₂N₄O₂ requires 402

Description 68: (S) 6,7-Difluoro-2-[(piperidin-2-ylmethyl)-amino]-quinoline-3-carbonitrile

[0250] The title compound (1.40 g) was prepared from the compound of D67 (1.8 g) according to the method of D9.

[0251] Mass spectrum (API⁺): Found 303 (MH⁺). C₁₆H₁₆F₂N₄ requires 302

Description 69: (S)2-[(5-Bromo-pyrimidin-2-ylamino)-methyl]-pyrrolidin-1-carboxylic acid tert butyl carbonate.

[0252] (S)-2-Aminomethyl-pyrrolidine-1-carboxylic acid tert butyl ester (2 g), 5-bromo-2-chloropyrimidine (1.93 g) were combined in xylene (40 ml) containing potassium carbonate (2.76 g) and diisopropylethylamine (5.23 ml) and warmed to reflux for 20 h. The mixture was cooled to room temperature, filtered and solvent removed at reduced pressure. The residue was column chromatographed (silica gel, pentane-25% ethyl acetate/pentane). The appropriate fractions were collected, solvent removed at reduced pressure to give the title compound (1.78 g) as a colourless gum

[0253] Mass spectrum (API⁺): Found 257 (MH⁺-tert BOC). C₁₄H₂₁BrN₄O₂ requires 357

Description 70: (S) (5-Bromo-pyrimidin-2-yl)-pyrrolidin-2-ylmethyl-amine

[0254] The title compound (1.40 g) was prepared from the compound of D69 (1.78 g) according to the method of D9.

[0255] Mass spectrum (API⁺): Found 258 (MH⁺). C₉H₁₂N₄Br requires 257.

Description 71: 3-(1-{(S)-2-[(6,7-Difluoro-quinoxalin-2-ylamino)-methyl]-piperidin-1-yl}-methanoyl)-benzoic acid

[0256] 3-(1-{(S)-2-[(6,7-Difluoro-quinoxalin-2-ylamino)-methyl]-piperidin-1-yl}-methanoyl)-benzoic acid methyl ester (0.5 g) was dissolved in methanol (15 ml) and treated with 1M sodium hydroxide (1.7 ml). The reaction mixture was stirred for 12 h, additional 1M sodium hydroxide (1.7 ml) added and stirring continued for a further 24 h The reaction mixture was diluted with water and washed with ethyl acetate. The aqueous phase was acidified with 2M hydrochloric acid and extracted with ethyl acetate (×3). the combined organic phase was dried (MgSO₄), fioltered and solvent removed at reduced pressure to give the title compound (0.463 g) as a yellow solid.

[0257] Mass spectrum (API⁺): Found 427 (MH⁺). C₂₂H₂₀F₂N₄O₃ requires 426.

Description 72: 1,1,1-Trifluoromethanesulphonic acid, 5-bromo-pyridin-2-yl ester

[0258] To a solution of 5-bromo-2-pyridone (3 g) in dichloromethane (60 ml) and pyridine (60 ml) at 0° C. under argon was added dropwise trifluoromethane sulphonic anhydride (5.4 g). The resulting mixture was warmed to ambient temperature and after 20 h was evaporated and the residue chromatographed on silica gel eluting with ethyl acetate to afford the title product (3.5 g) as a yellow oil. ¹H NMR δ: 7.10 (1H, d,J=8 Hz), 8.00 (1H, dd, 2.4 and 8 Hz), 8.46 (1H, d,J=2.4 Hz).

Description 73: (S)-2-[(5-Bromopyridin-2-ylamino)-methyl]-pyrrolidine-1-carboxylic acid tert-butyl ester

[0259] The title product (0.22 g) was obtained from (S)-2-aminomethyl-pyrrolidine-1-carboxylic acid tert butyl ester (1 g) and the compound of D72 (1.7 g) according to the method of D69.

[0260] Mass Spectrum (Electrospray LC/MS), API⁺: Found 356 (MH⁺). C₁₅H₂₂ ⁷⁹BrN₃O₂ requires 355.

Description 74: (5-Bromo-pyridin-2-yl)-(S)-1-pyrrolidin-2-ylmethylamine

[0261] To a solution of the compound from D73 (0.49 g) in dichloromethane (40 ml) at ambient temperature was added trifluoroacetic acid (5 ml). After 48 h, the reaction mixture was evaporated and partitioned between chloroform and 1M sodium hydroxide. The aqueous layer was extracted with chloroform and the combined organic extracts dried and evaporated to afford the tide compound (0.33 g) as an orange oil. ¹H NMR δ: 1.44-1.48 (1H, m), 1.71-1.81 (3H, m), 2.05 (1H, br s), 2.93 (2H, m), 3.09-3.13 (1H, m), 3.35-3.41 (2H, m), 4.99 (1H, br s), 6.32 (1H, d,J=9 Hz), 7.43 (1H, dd, J=3 and 9 Hz), 8.08 (1H, d, J=3 Hz).

Description 75: N-(4-Benzyl-morpholin-3-ylmethyl)-2,2,2-trifluoroacetamide

[0262] To (4-benzyl-morpholin-3-yl)-methylamine (7.34 g) in dichloromediane (240 ml) was added triethylamine (5.83 ml), followed by dropwise addition of trifluoroacetic anhydride (8.23 g) over 25 min at 0° C. under argon. The reaction mixture was allowed to reach ambient temperature and after stirring for 18 h, was diluted in dichloromethane and washed with saturated aqueous sodium hydrogencarbonate. The organic phase was separated, dried and evaporated to afford a brown gum that was purified on silica gel, eluting with ethyl acetate-pentane mixtures to afford the title product (5.17 g) as an orange gum. Mass Spectrum (API⁺): Found 303 (MH⁺). C₁₄H₁₇F₃N₂O₂requires 302.

Description 76: 2,2,2-Trifluoro-N-morpholin-3-ylmethyl acetamide

[0263] To the compound from D75 (1.62 g) in methanol (40 ml) was added palladium black (0.45 g) and formic acid (10 drops) and the mixture stirred at ambient temperature for 16 h. Further palladium black (0.225 g) and formic acid (10 drops) were added and after 1 h, the reaction mixture was filtered through kieselguhr and the filtrate evaporated to an orange gum. Re-evaporation from dichloromethane provided the title compound (1.4 g) as a pink solid. Mass Spectrum (API⁺): Found 213 (MH⁺). C₇H₁₁F₃N₂O₂ requires 212.

Description 77: 3-[(2,2,2-Trifluoro-ethanoylamino)methyl]-morpholine4-carboxylic acid tert-butyl ester

[0264] A mixture of the compound from D76 (1.75 g), triethylamine (2.25 ml) and di-tert-butyl dicarbonate (3.59 g) in dichloromethane (75 ml) was stirred at ambient temperature for 18 h. The reaction mixture was diluted with dichloromethane and washed successively with 2M hydrochloric acid, water and brine, dried and evaporated to a gum. Chromatography on silica gel eluting with ethyl acetate-pentane mixtures afforded the title compound (1.70 g) as a pale yellow solid. Mass Spectrum (API⁺): Found 213 (MH-¹Boc)⁺. C₁₂H₁₉F₃N₂O₄ requires 312.

Description 78: 3-Aminomethyl-morpholine4-carboxylic acid tert-butyl ester

[0265] A mixture of the compound from D77 (1.7 g) and potassium carbonate (3.77 g) in methanol (80 ml) and water (27 ml) was stirred at ambient temperature for 4 h and then heated at 50° C. for a further 2 h The reaction mixture was concentrated to remove methanol, diluted with water and extracted with ethyl acetate (×3) and dichloromethane (×4). The combined extracts were dried and evaporated to afford the title product (0.97 g) as a yellow gum. Mass Spectrum (API⁺): Found 116 (MH-^(t)Boc)⁺. C₁₀H₂₀N₂O₃ requires 216.

Description 79: 3-[(5Bromo-pyrimidin-2-ylamino)-methyl]-morpholine4-carboxylic acid tert-butyl ester

[0266] The title compound (1.19 g) was obtained from the compound of D78 (0.97 g) and 5-bromo-2-chloropyrimidine (0.87 g) according to the method of D30. Mass spectrum (API⁺): Found 273 (MH⁺-^(t)Boc). C₁₄H₂₁ ⁷⁹BrN₄O₃ requires 372.

Description 80: (5-Bromo-pyrimidin-2-yl)-morpholin-3-ylmethyl amine

[0267] To the compound of D79 (1.15 g) in dichloromethane (45 ml) at 0° C. was added trifluoroacetic acid (5 ml) and the reaction mixture then stirred at ambient temperature for 2 h. The resulting solution was poured onto ice and saturated aqueous potassium carbonate solution, and then extracted with dichloromethane (×2). The organic extracts were dried and evaporated to afford the title product (0.85 g) as an off white solid. Mass Spectrum (API⁺): Found 273 (MH⁺). C₉H₁₃ ⁷⁹BrN₄O requires 272.

Description 81: (S)-2-[(4-Cyano-2,6-difluorophenylamino)-methyl]-piperidine-1-carboxylic acid tert-butyl ester

[0268] (S)-2-Aminomethyl-piperidine-1-carboxylic acid tert-butyl ester (1.36 g) and 3,4,5-trifluorobenzonitrile (1.00 g) were heated under argon in xylene (10 ml) containing diisopropylethylamine (3.3 ml) for 16 h. The reaction mixture was cooled and partitioned between ethyl acetate and water. The organic phase was washed with brine, dried and evaporated to give a solid which was triturated with pentane-ether to afford the title product (0.16 g) as an off white powder. Chromatography of the mother liquors on silica gel eluting with ethyl acetate-pentane mixtures afforded further title product (0.92 g). Mass Spectrum (API⁺): Found 252 (MH⁺-^(t)Boc). C₁₈H₂₃F₂N₃O₂ requires 351.

Description 82: 3,5-Difluoro4-[((S)-1-piperidin-2-ylmethyl)-amino]-benzonitrile

[0269] Trifluoroacetic acid (3 ml) was added to a solution of D81 (1.05 g) in dichloromethane (27 ml) at 0° C. The reaction was allowed to reach ambient temperature, stirred for 4 h and then poured into saturated aqueous potassium carbonate. The aqueous phase was extracted with dichloromethane and the combined extracts dried and evaporated to afford the title compound (0.59 g) as an off white solid. Mass Spectrum (API⁺): Found 252 (MH⁺). C₁₃H₁₅F₂N₃ requires 251.

Description 83: (S)-2-[(4-Cyano-2,6-difluoro-phenylamino)-methyl]-pyrrolidine-1-carboxylic acid tert-butyl ester

[0270] The title compound (0.295 g) was obtained from (S)-2-aminomethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (0.402 g) and 3,4,5-trifuorobenzonitrile (0.314 g) using a similar procedure to that described in Description 81. Mass Spectrum (API⁺): Found 238 (MH⁺-^(t)Boc) C₁₇H₂₁F₂N₃O₂ requires 337.

Description 84: 3,5-Difluoro4-[((S)-1-pyrrolidin-2-ylmethyl)-amino]-benzonitrile

[0271] The title compound (0.19 g) was obtained from the compound of D83 (0.28 g) using a similar procedure to that described in Description 82.

Description 85: (S)-2-[(5-Ethyl-pyrimidin-2-ylamino)-methyl]-pyrrolidine-1-carboxylic acid tert-butyl ester

[0272] The title compound (0.10 g) was obtained from (S)2-aminomethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (0.75 g) and 2-chloro-5-ethyl pyrimidine (0.53 g) using a similar procedure to that described in description 81. Mass Spectrum (Electrospray LC/MS): Found 307 (MH⁺). C₁₆H₂₆N₄O₂ requires 306.

Description 86: (5-Ethyl-pyrimidin-2-yl)-(S)-1-pyrrolidin-2-ylmethylamine

[0273] The title compound (0.07 g) was obtained from the compound of D85 (0.10 g) using the method of D9. Mass Spectrum (Electrospray LC/MS): Found 207 (MH⁺). C₁₁H₁₈N₄ requires 206.

Description 87: (S)-2-[(2,2,2-Trifluoro-ethanoylamino)-methyl]-pyrrolidine-1-carboxylic acid tert-butyl ester

[0274] To a solution of (S)-2-aminomethyl pyrrolidine-1-carboxylic acid tert-butyl ester (1.3 g) in dichloromethane (50 ml) containing triethylamine (1.4 ml) was added trifluoroacetic anhydride (1.6 g) dropwise under argon. After 16 h at ambient temperature the reaction mixture was diluted with dichloromethane and washed with brine. The aqueous layer was extracted with dichloromethane and the combined extracts dried and evaporated. Chromatography of the residue on silica gel eluting with pentane-ethyl acetate mixture afforded the title compound (1.43 g) as an orange oil. ¹H NMR δ: 1.30-1.50 (1H, m), 1.47 (9H, s), 1.60-1.75 (1H, m), 1.80-1.95 (2H, m), 2.00-2.10 (1H, m), 3.22-3.30 (1H, m) 3.30-3.55 (3H, m), 9.03 (1H, br s).

Description 88: (S)-2-{[Methyl-2,2,2-trifluoro-ethanoyl)-amino]-methyl}-pyrrolidine-1-carboxylic acid tert-butyl ester

[0275] Sodium hydride (0.23 g, 60% dispersion in oil) was added to a solution of the compound of D87 (1.4 g) in dimethylformamide (30 ml) under argon. After 1 h, iodomethane (0.32 ml) was added and the reaction mixture stirred for a firer 16 h before being partitioned between ethyl acetate and water. The aqueous layer was extracted with ethyl acetate and the combined extracts washed with brine, dried and evaporated to give the title compound (1.6 g) as an orange oil. Mass Spectrum (API⁺): Found 311 (MH⁺); C₁₃H₂₁F₃N₂O₃ requires 310.

Description 89: (S)-2-Methylaminomethyl-pyrrolidine-1-carboxylic acid tert-butyl ester

[0276] A mixture of the compound of D88 (1.47 g) and 1M potassium carbonate (20 ml) in methanol (50 ml) was stirred at ambient temperature for 20 h. After removal of the methanol in vacuo, the residue was partitioned between chloroform and water. The aqueous layer was extracted with chloroform and the combined extracts dried and evaporated to afford the title product (0.82 g) as an orange oil.

Description 90: (S)-2-{[(5-Bromo-pyrimidin-2-yl)-methyl-amino]-methyl}-pyrrolidine-1-carboxylic acid tert-butyl ester

[0277] The title product (0.85 g) was obtained from the compound of D89 (0.82 g) and 5-bromo-2-chloro pyrimidine (0.77 g) in a similar manner to that described in the procedure of description 81. Mass Spectrum (API⁺): Found 371 (MH⁺). C₁₅H₂₃ ⁷⁹BrN₄O₂ requires 370.

Description 91: (5-Bromo-pyrimidin-2-yl)-methyl-(S)-1-pyrrolidin-2-yl)methylamine

[0278] A solution of the compound from D90 (0.82 g) in dichloromethane (50 ml) and trifluoroacetic acid (10 ml) was stirred at ambient temperature for 20 h. evaporated and partitioned between ethyl acetate and 1M sodium hydroxide. The organic phase was separated, dried and evaporated to afford the title product as an orange oil (0.54 g). Mass Spectrum (API⁺): Found 271 (MH⁺). C₁₀H₁₅ ⁷⁹BrN₄ requires 270.

Description 92: (S)-2-[(5-Acetyl-pyrimidin-2-ylamino)-methyl]-pyrrolidine-1-carboxylic acid tert-butyl ester

[0279] The title compound (0.57 g) was prepared from the compound of D69 (1.06 g) (1-ethoxyvinyl)tributyl tin (1.2 ml) and tetrakis (triphenylphosphine)palladium (0) (0.172 g) according to the method of Example 171. Mass Spectrum (API⁺): Found 321 (MH⁺). C₁₆H₂₄N₄O₃ requires 320.

Description 93: 1-{2-[((S)-1-Pyrroldin-2-ylmethyl)amino]-pyrimidin-5yl}-ethanone trifluoroacetate

[0280] To a solution of the compound of D92 (0.57 g) in dichloromethane (18 ml) at 0° C. was added trifluoroacetic acid (2 ml) dropwise. The reaction mixture was stirred at ambient temperature for 2 h, and evaporated to afford the title compound as a yellow gum (1.13 g). Mass Spectrum (API⁺): Found 221 (MH⁺). C₁₁H₁₆N₄O requires 220.

Description 94: (S)-2-[(5Chloro-pyrimidin-2-ylamino)methyl]-pyrrolidine-1-carboxylic acid tert-butyl ester

[0281] (S)-2-Aminomethyl pyrrolidine-1-carboxylic acid tert-butyl ester (3.38 g), 2,5-dichloropyrimidine (2.50 g), potassium carbonate (4.67 g) and diisopropylethylamine (8.79 ml) were heated in xylene (60 ml) at 100° C. for 3.75 h. The cooled reaction mixture was filtered and the filtrate evaporated to a gum which was chromatographed on silica gel, eluting with ethyl acetate-pentane fractions, to afford the title compound as a pale yellow solid (2.55 g). Mass Spectrum (API⁺): Found 213 (MH⁺-^(t)Boc). C₁₄H₂₁ ³⁵CIN₄O₂ requires 312.

Description 95: (5-Chloro-pyrimidin-2-yl)-(S)-1-pyrrolidin-2-ylmethylamine

[0282] The compound of D94 (2.5 g) was dissolved in dichloromethane (63 ml), cooled to 0° C. and trifluoroacetic acid (7 ml) added dropwise. The reaction mixture was stirred at ambient temperature for 2 h, recooled to 0° C. and further trifluoroacetic acid (3 ml) added. After 2 h at ambient temperature the mixture was carefully poured into ice-saturated potassium carbonate and the organic layer separated. The aqueous phase was extracted with dichloromethane (×4) and the combined extracts dried and evaporated to afford the title product (1.74 g) as an orange solid. Mass Spectrum (Electrospray LC/MS): Found 213 (MH⁺). C₉H₁₃ ³⁵CIN₄ requires 212.

Description 96: (S)-2-[(5-Cyano-pyridin-2-ylamino)-methyl]-pyrrolidine-1-carboxylic acid tert-butyl ester

[0283] (S)-2-Aminomethyl pyrrolidine-1-arboxylic acid tert-butyl ester (0.3 g), 6-chloronicotinonitrile (0.21 g), potassium carbonate (0.41 g) and diisopropylethylamine (0.78 ml) were heated in xylene at 130° C. for 26 h, cooled and the mixture filtered through kieselguhr. The filtrate was evaporated and the residue chromatographed on silica gel, eluting with ethyl acetate-hexane mixtures to afford the title compound (0.2 g). Mass Spectrum (API⁺): Found 303 (MH⁺). C₁₆H₂₂N₄O₂ requires 302.

Description 97: 6-[((S)-1-Pyrrolidin-2-ylmethyl)-amino]-nicotinonitrile

[0284] A solution of the compound of D96 (0.2 g) in dichloromethane (20 ml) and trifluoroacetic acid (2.5 ml) was stirred at ambient temperature for 2 h., evaporated and partitioned between dichloromethane and 1M sodium hydroxide. The aqueous phase was extracted with dichloromethane and the combined extracts dried and evaporated to afford the title compound as a gum (0.137 g). Mass Spectrum (Electrospray LC/MS): Found 203 (MH⁺). C₁₁H₁₄N₄ requires 202.

Description 98: 1,1,1-Trifluoromethanesulfonic acid 6-methyl-2-methylsulfanyl-pyrimidin-4-yl ester

[0285] To a solution of 6-methyl-2-methylsulfanyl-pyrimidin-4-ol (1 g) in dichloromethane (40 ml) containing triethylamine (1.35 ml) at 0° C. under argon was added trifluoromethanesulphonic anhydride (1.46 ml) dropwise. The resulting solution was allowed to reach ambient temperature and stirred for 16 h. before being partitioned between dichloromethane and saturated aqueous sodium hydrogen carbonate solution. The organic phase was washed with brine, dried and evaporated and the residue chromatographed on silica gel, eluting with ethyl acetate-pentane mixtures, to afford the title compound (0.8 g). ¹H NMR δ: 2.53 (3H, s), 2.55 (3H, s), 6.63 (1H, s).

Description 99: 2,2,2-Trifluoro-N-(S)-1-pyrrolidin-2-ylmethyl-acetamide

[0286] The title compound (2.31 g) was obtained from the compound of D87 (5.5 g) using the method of D97. ¹H NMR δ: 1.30-1.50 (1H, m), 1.70-1.95 (3H, m), 2.20 (1H, br s), 2.85 -2.90 (1H, m), 2.94-2.97 (1H, m), 3.07-3.12 (1H, m), 3.37- 3.39 (1H, m), 3.44-3.48 (1H, m), 7.15 (1H, br s).

Description 100: 2,2,2-Trifluoro-N-((S)-1-{1-[5-(4-fluorophenyl)-2-methyl-thiazol4-yl]-methanoyl}-pyrrolidin-2-ylmethyl)-acetamide

[0287] The title compound (3.84 g) was obtained from the compound of D99 (2.31 g) and 5-(4-fluorophenyl)-2-methyl-thiazole-4-carboxylic acid (3.08 g) using the method of Example 229. Mass Spectrum (Electrospray LC/MS): Found 416 (MH⁺). C₁₈H₁₇F₄N₃O₂S requires 415.

Description 101: 1-((S)-2-Aminomethyl-pyrrolidin-1-yl)-1-[5-(4-fluoro-phenyl)-2-methyl-thiazol4-yl]-methanone

[0288] The title compound (2.45 g) was obtained from the compound of D100 (3.84 g) using a similar procedure to that described in D78. Mass Spectrum (Electrospray LC/MS): Found 320 (MH⁺). C₁₆H₁₈FN₃OS requires 319.

Description 102: 3-[(2,2,2-Trifluoro-ethanoylamino)-methyl]-morpholine-4-carboxylic acid tert-butyl ester

[0289] The title compound (0.56 g) was obtained from the compound of D77 (0.55 g) and iodomethane (0.12 ml) using a method similar to that of Description 88. Mass Spectrum (API⁺): Found 227 (MH⁺-^(t)Boc). C₁₃H₂₁F₃N₂O₄ requires 326.

Description 103: 3-Methylaminomethyl-morpholine-4-carboxylic acid tert-butyl ester

[0290] The title compound (0.29 g) was obtained from the compound of D102 (0.56 g) using the method of Description 89.

Description 104: 3-{[(5-Bromo-pyrimidin-2-yl)-methyl-amino]-methyl}-morpholine-4-carboxylic acid tert-butyl ester

[0291] The title compound (0.3 g) was obtained from the compound of D103 (0.29 g) and 5-bromo-2-chloropyrimidine (0.26 g) using the method of Description 81. Mass Spectrum (Electrospray LC/MS): Found 287 (MH⁺-^(t)Boc). C₁₅H₂₃ ⁷⁹BrN₄O₃ requires 386.

Description 105: (5-Bromo-pyrimidin-2-yl)-methyl-morpholin-3-ylmethyl-amine

[0292] The title compound (0.19 g) was obtained from the compound of D104 (0.3 g) according to the method of Description 91. Mass Spectrum (API⁺): Found 287 (MH⁺). C₁₀H₁₅ ⁷⁹BrN₄O requires 286.

EXAMPLE 1 1-[2-Benzoxazol-2-ylaminomethyl)-piperidin-1-yl]-1-(2-methyl-5phenyl-thiazol4-yl)-methanone

[0293] The amine of D3 (0.11 g), triethylamine (0.05 g) and 2-methyl-5-phenyl-thiazole4-carbonyl chloride (0.12 g) were combined in dichloromethane (5 ml) and shaken for 16 hours. The organic phase was washed with water, filtered through a Whatman phase-separation filter tube, solvent removed at reduced pressure to give after column chromatography (silica gel, 0-10% (9:1 methanol/ammonia) in dichloromethane eluant) the title compound (0.13 g).

[0294] Mass Spectrum (API⁺): Found 433 (MH⁺). C₂₄H₂₄N₄O₂S requires 432.

[0295] The compounds of the Examples below were prepared from the appropriate amine and acid chloride using a similar procedure to that described in Example. 1. Mass Spectrum (Electrospray LC/MS) Example Amine Y Ar² Ar¹ API⁺ 2 D3 CH₂

Found 412 (MH⁺). C₂₆H₂₅N₃O₂ requires 411 3 D3 CH₂

Found 418 (MH⁺). C₂₃H₂₃N₅O₃ requires 417 4 D3 CH₂

Found 420 (MH⁺). C₂₁H₂₀F₃N₃O₃ requires 419 5 D3 CH₂

Found 386 (MH⁺). C₂₄H₂₃N₃O₂ requires 385 6 D3 CH₂

Found 366 (MH⁺). C₂₁H₂₃N₃O₃ requires 365 7 D3 CH₂

Found 462 (MH⁺). C₂₀H₂₀IN₃O₂ requires 461 8 D5 CH₂

Found 420 (MH⁺). C₂₁H₂₀F₃N₃O₃ requires 419 9 D5 CH₂

Found 418 (MH⁺). C₂₃H₂₃ N₅O₃ requires 417 10 D5 CH₂

ound 412 (MH⁺). Cd₂₆H₂₅N₃O₂ requires 411 11 DS CH₂

Found 462 (MH⁺). C₂₀H₂₀IN₃O₂ requires 461 12 D3 CH₂ Ph

Found 336 (MH⁺). C₂₀H₂₁N₃O₂ requires 335 13 D9 CH₂

Found 450 (MH⁺). C₂₄H₂₄FN₅OS requires 449 14 D9 CH₂

Found 417 (MH⁺). C₂₅ H₂₄N₆O_(2 requires 416) 15 D13 CH₂

Found 434 (MH⁺). C₂₃H₂₃N₅O₂S requires 433 16 D13 CH₂

Found 436 (MH⁺). C₂₁H₂₀F₃N₃O₂S requires 435 17 D13 CH₂

Found 428 (MH⁺). C₂₆H₂₅N₃OS requires 427 18 D13 CH₂

Found 449 (MH⁺). C₂₄H₂₄N₄OS₂ requires 448 19 D15 CH₂

Found 461 (MH⁺). C₂₆H₂₅FN₄OS requires 460 20 D15 CH₂

Found 428 (MH⁺). C₂₅H₂₅N₅O₂ requires 427 21 D15 CH₂

Found 430 (MH⁺). C₂₃H₂₂F₃N₃O₂ requires 429 22 D15 CH₂

Found 472 (MH⁺). C₂₂H₂₂IN₃O requires 471 23 D15 CH₂

Found 396 (MH⁺). C₂₆H₂₅N₃O requires 395 24 D19 CH₂

Found 431 (MH⁺). C₂₂H₂₁F₃N₄O₂ requires 430 25 D19 CH₂

Found 431 (MH⁺). C₂₂H₂₁F₃N₄O₂ requires 430 26 D19 CH₂

Found 473 (MH⁺). C₂₁H₂₁IN₄O requires 472 27 D19 CH₂

Found 462 (MH⁺). C₂₅H₂₄FN₅OS requires 461 28 D19 CH₂

Found 429 (MH⁺). C₂₄H₂₄N₆O₂ requires 428 29 D33 CH₂

Found 462 (MH⁺). C₂₅H₂₄FN₅OS requires 461 30 D35 CH₂

Found 462 (MH⁺). C₂₅H₂₄FN₅OS requires 461 31 D37 CH₂

Found 462 (MH⁺). C_(25 H) ₂₄FN₅OS requires 461

EXAMPLE 32 1-[(S)-2-(Benzoxazol-2-ylaminomethyl)-piperidin-1-yl]-1-[5-(4-fluoro-phenyl-2-methyl-thiazol4-yl]methanone

[0296] A mixture of amine D5 (0.05 g), 2-methyl-5-phenyl-thiazole-4-carboxylic acid (0.026 g) and diisopropylethylamine (0.06 ml) in dimethylformamide (5 ml) was treated with [(O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate] (0.042 g) and the mixture stirred for 48 hours. The mixture was diluted with ethyl acetate, washed with sodium hydrogen carbonate and water, dried, solvent removed at reduced pressure and the residue column chromatographed (silica gel, dichloromethane—1% methanol/dichloromethane) to give the title compound (0.05 g).

[0297] Mass Spectrum (API⁺): Found 451 (MH⁺). C₂₄H₂₃FN₄O₂S requires 450.

[0298] The compounds of the Examples below were prepared from the appropriate amine and acid using similar procedures to that described in Example 32.

Mass Spectrum (Electrospray LC/MS), Example Amine Y Ar² Ar¹ AP⁺ 33 D7 O

Found 420 (MH⁺). C₂₂H₂₁N₅ _(O) ₄ requires 419 34 D11 CH₂

Found 461 (MH⁺). C₂₆H₂₅FN₄OS requires 460 35 D11 CH₂

Found 428 (MH⁺). C₂₅H₂₅N₅O₂ requires 427 Prepared as the HCl salt 36 D11 CH₂

Found 430 (MH⁺). C₂₃H₂₂F₃N₃O₂ requires 429 Prepared as the HCl salt 37 D13 CH₂

Found 402 (MH⁺). C₂₄H₂₃N₃OS requires 401 38 D17 CH₂

Found 461 (MH⁺). C₂₆H₂₅FN₄OS requires 460 39 D21 CH₂

Found 412 (MH⁺). C₂₁H₂₂FN₅OS requires 411 40 D21 CH₂

Found 379 (MH⁺). C₂₀H₂₂N₆O₂ requires 378 41 D23 CH₂

Found 412 (MH⁺). C₂₁H₂₂FN₅OS requires 411 42 D25 CH₂

Found 462 (MH⁺). C₂₅H₂₄FN₅OS requires 461 43 D25 CH₂

Found 448 (MH⁺). C₂₄H₂₂FN₅OS requires 447 44 D25 CH₂

Found 445 (MH⁺). C₂₅H₂₅FN₆O requires 444 45 D25 CH₂

Found 445 (MH⁺). C₂₅H₂₅FN₆O requires 444 46 D25 CH₂

Found 431 (MH⁺). C₂₄H₂₃FN₆O requires 430 47 D25 CH₂

Found 462 (MH⁺). C₂₅H₂₄FN₅OS requires 461 48 D25 CH₂

Found 446 (MH⁺). C₂₄H₂₄FN₇O requires 445 49 D25 CH₂

Found 397 (MH⁺). C₂₅H₂₄N₄O requires 396 50 D25 CH₂

Found 456 (MH⁺). C₂₂H₂₃ ⁷⁹BrN₄O₂ requires 455 51 D25 CH₂

Found 429 (MH⁺). C₂₄H₂₄N₆O₂ requires 428 52 D25 CH₂

Found 431 (MH₊). C₂₂H₂₁F₃N₄O₂ requires 430 53 D27 CH₂

Found 512 (MH⁺). C₂₆H₂₄F₃N₅OS requires 511 54 D27 CH₂

Found 498 (MH⁺). C₂₅H₂₂F₃N₅OS requires 497 55 D27 CH₂

Found 495 (MH⁺). C₂₆H₂₅F₃N₆O requires 494 56 D27 CH₂

Found 481 (MH⁺). C₂₅H₂₃F₃N₆O requires 480 57 D27 CH₂

Found 495 (MH⁺). C₂₆H₂₅F₃N₆O requires 494 58 D27 CH₂

Found 495 (MH⁺). C₂₆H₂₅F₃N₆O requires 494 59 D27 CH₂

Found 447 (MH⁺). C₂₆H₂₄F₂N₄O requires 446 60 D29 CH₂

Found 434 (MH⁺). C₂₄H₂₁F₂N₅O requires 433 61 D29 CH₂

Found 482 (MH⁺). C₂₅H₂₂F₃N₅O₂ requires 481 62 D29 CH₂

Found 498 (MH⁺). C₂₅H₂₂F₃N₅OS requires 497 63 D29 CH₂

Found 465 (MH⁺). C₂₄H₂₂F₂N₆O₂ requires 464 64 D29 CH₂

Found 467 (MH⁺). C₂₂H₁₉F₅N₄O₂ requires 466 65 D29 CH₂

Found 459 (MH⁺). C₂₇H₂₄F₂N₄O requires 458 66 D29 CH₂

Found 491 (MH⁺). C₂₂H₂₁ ⁷⁹BrF₂N₄O₂requires 490 67 D29 CH₂

Found 481 (MH⁺). C₂₅H₂₃F₃N₆O requires 480 68 D29 CH₂

Found 481 (MH⁺). C₂₅H₂₃F₃N₆O requires 480 69 D29 CH₂

Found 482 (MH⁺). C₂₄H₂₂F₃N₇O requires 481 70 D29 CH₂

Found 433 (MH⁺). C₂₅H₂₂F₂N₄O requires 432 71 D29 CH₂

Found 484 (MH⁺). C₂₄H₂₀F₃N₅OS requires 483 72 D33 CH₂

Found 445 (MH⁺). C₂₅H₂₅FN₆O requires 444 73 D39 CH₂

Found 419 (MH⁺). C₂₂H₂₂N₆O₃ requires 418 74 D39 CH₂

Found 421 (MH⁺). C₂₀H₁₉F₃N₄O₃ requires 420 75 D39 CH₂

Found 452 (MH⁺). C₂₃H₂₂FN₅O₂S requires 451 76 D39 CH₂

Found 463 (MH⁺). C₁₉H₁₉N₄O₂ requires 462 77 D47 CH₂

Found 500 (MH⁺). C₂₄H₂₀F₃N₅O₂S requires 499 78 D47 CH₂

Found 483 (MH⁺). C₂₄H₂₁F₃N₆O₂ requires 482 79 D47 O

Found 483 (MH⁺). C₂₄H₂₁F₃N₆O₂ requires 482 80 D49 CH₂

Found 463 (MH⁺). C₂₄H₂₃FN₆OS requires 462 81 D50 CH₂

Found 463 (MH⁺). C₂₄H₂₃FN₆OS requires 462 82 D53 CH₂

Found 493 (MH⁺). C₂₆H₂₅FN₄OS₂ requires 492 83 D29 CH₂

Found 435 (MH⁺). C₂₃H₂₀F₂N₆O requires 434 84 D29 CH₂

Found 434 (MH⁺). C₂₄H₂₁F₂N₅O requires 433 85 D29 CH₂

Found 434 (MH⁺). C₂₄H₂₁F₂N₅O requires 433 86 D29 CH₂

Found 414 (MH⁺). C₂₁H₂₁F₂N₅O₂ requires 413 87 D29 CH₂

Found 435 (MH⁺). C₂₃H₂₀F₂N₆O requires 434 88 D55 CH₂

Found 419 (MH⁺). C₂₃H₂₃FN₆O requires 418 89 D57 CH₂

Found 480 (MH⁺). C₂₂H₂₁F₄N₅OS requires 479 90 D49 CH₂

Found 388 (MH⁺). C₂₁H₂₁N₇O requires 387 91 D29 CH₂

Found 527 (MH⁺). C₂₆H₂₅F₃N₆OS requires 526 92 D29 CH₂

Found 484 (MH⁺). C₂₆H₃₁F₂N₅O₂ requires 483 109 D29 CH₂

Found 441 (MH⁺). C₂₃H₁₉F₃N₄O₂ requires 440 110 D62 CH₂

Found 436 (MH⁺). C₂₃H₂₂FN₅OS requires 435 111 D62 CH₂

Found 403 (MH⁺). C₂₂H₂₂N₆O₂ requires 402 112 D64 CH₂

Found 436 (MH⁺). C₂₃H₂₂FN₅OS requires 435 113 D29 CH₂

Found 439 (MH⁺). C₂₃H₂₀F₂N₄OS requires 438 114 D29 CH₂

Found 423 (MH⁺). C₂₂H₂₀F₂N₆O requires 422 115 D29 CH₂

Found 424 (MH⁺). C₂₁H₁₉F₂N₇O requires 423 116 D29 CH₂

Found 440 (MH⁺). C₂₂H₁₉F₂N₅OS requires 439 117 D29 CH₂

Found 452 (MH⁺). C₂₁H₁₈Cl₂F₂N₄O requires 451 118 D29 CH₂

Found 443 (MH⁺). C₂₁H₂₄F₂N₄O₃ requires 451 121 D49 CH₂

Found 399 (MH⁺). C₂₃H₂₂N₆O requires 398 122 D49 CH₂

Found 387 (MH⁺). C₂₂H₂₂N₆O requires 386 123 D49 CH₂

Found 399 (MH⁺). C₂₃H₂₂N₆O requires 398 124 D29 CH₂

Found 525 (MH⁺). C₂₇H₂₇F₃N₆O₂ requires 524 125 D29 CH₂

Found 418 (MH⁺). C₂₀H₂₁F₂N₅OS requires 417 126 D29 CH₂

Found 482 (MH⁺). C₂₄H₂₂F₃N₇O requires 481 127 D55 CH₂

Found 463 (MH⁺). C₂₅H₂₇FN₆O₂ requires 462 128 D66 CH₂

Found 490 (MH⁺). C₂₁H₂₁ ⁷⁹BrFN₅OS requires 489 129 D66 CH₂

Found 459 (MH⁺). C₂₀H₂₀ ⁷⁹BrFN₆O requires 458 130 D66 CH₂

Found 460 (MH⁺). C₁₉H₁₉BrFN₇O requires 459 131 D66 CH₂

Found 426 (MH⁺). C₂₀H₂₀ ⁷⁹BrN₅O requires 425 132 D66 CH₂

Found 474 (MH⁺). C₂₀H₂₁ ⁷⁹BrFN₇O requires 473 133 D66 CH₂

Found 506 (MH⁺). C₂₁H₂₁ ⁷⁹BrFN₅O₂S requires 505 134 D66 CH₂

Found 457 (MH⁺). C₂₀H₂₁ ⁷⁹BrN₆O₂ requires 456 135 D66 CH₂

Found 426 (MH⁺). C₂₀H₂₀ ⁷⁹BrN₅O requires 425 136 D68 CH₂

Found 447 (MH⁺). C₂₄H₂₀F₂N₆O requires 446 137 D68 CH₂

Found 458 (MH⁺). C₂₄H₂₁F₂N₅O requires 457 138 D68 CH₂

Found 522 (MH⁺). C₂₇H₂₂F₃N₅OS requires 521 139 D68 CH₂

Found 457 (MH⁺). C₂₇H₂₂F₂N₄O requires 456 140 D68 CH₂

Found 491 (MH⁺). C₂₆H₂₁F₃N₆O requires 490 141 D68 CH₂

Found 446 (MH⁺). C₂₅H₂₁F₂N₅O requires 445 142 D68 CH₂

Found 464 (MH⁺). C₂₄H₁₉F₂N₅OS requires 463 143 D29 CH₂

Found 433 (MH⁺). C₂₅H₂₂F₂N₄O requires 432 144 D29 CH₂

Found 441 (MH⁺). C₂₃H₁₉F₃N₄O₂ requires 440 145 D29 CH₂

Found 441 (MH⁺). C₂₃H₁₉F₃N₄O₂ requires 440 146 D29 CH₂

Found 441 (MH⁺). C₂₃H₁₉F₃N₄O₂ requires 440 147 D29 CH₂

Found 459 (MH⁺). C₂₃H₁₈F₄N₄O₂ requires 458 148 D62 CH₂

Found 405 (MH⁺). C₂₂H₂₁FN₆O requires 404 149 D62 CH₂

Found 419 (MH⁺). C₂₃H₂₃FN₆O requires 418 150 D64 CH₂

Found 419 (MH⁺). C₂₃H₂₃FN₆O requires 418 151 D66 CH₂

Found 558 (MH⁺). C₂₆H₃₂ ⁷⁹BrN₅O₂S requires 557 152 D29 CH₂

Found 566 (MH⁺). C₃₀H₃₃F₂N₅O₂S requires 565 153 D29 CH₂

Found 427 (MH⁺). C₂₀H₂₀BrN₅O requires 426 154 D29 CH₂

Found 436 (MH⁺). C₂₄H₂₃F₂N₅O requires 435 155 D29 CH₂

Found 422 (MH⁺). C₂₃H₂₁F₂N₅O requires 421 156 D29 CH₂

Found 441 (MH⁺). C₂₁H₁₈F₂N₆OS requires 440 157 D29 CH₂

Found 441 (MH⁺). C₂₃H₂₂F₂N₄O₃ requires 440 158 D29 CH₂

Found 538 (MH⁺). C₂₈H₃₀F₃N₇O requires 537 159 D66 CH₂

Found 530 (MH⁺). C₂₄H₂₉ ⁷⁹BrFN₇O requires 529 160 D49 CH₂

Found 490 (MH⁺). C₂₆H₂₈FN₇O₂ requires 489 161 D49 CH₂

Found 388 (MH⁺). C₂₁H₂₁N₇O requires 387 162 D66 CH₂

Found 415 (MH⁺). C₁₈H₁₉ ⁷⁹BrN₆O requires 414 163 D66 CH₂

Found 415 (MH⁺). C₁₉H₁₉ ⁷⁹BrN₄O₂ requires 414 164 D66 CH₂

Found (MH⁺). 405 C₁₈H₂₁ ⁷⁹BrN₄O₂ requires 404 165 D66 CH₂

Found 426 (MH⁺). C₂₀H₂₀ ⁷⁹BrN₅O requires 425 166 D29 CH₂

Found 484 (MH⁺). C₂₆H₃₁F₂N₅O₂ requires 483 170 D66 CH₂

Found 473 (MH⁺). C₂₁H₂₂ ⁷⁹BrFN₆O requires 472 175 D66 CH₂

Found 375 (MH⁺). C₁₇H₁₉ ⁷⁹BrN₄O requires 374. 199 D7 O

Found 420 (MH⁺). C₂₂H₂₁N₅O₄ requires 419 204 D82 CH₂

Found 454 (MH⁺). C₂₄H₂₂F₃N₅O requires 453 206 D82 CH₂

Found 438 (MH⁺). C₂₃H₂₁F₂N₅O₂ requires 437 207 D82 CH₂

Found 396 (MH⁺). C₂₂H₁₉F₂N₃O₂ requires 395 230 D66 CH₂

Found 446 (MH⁺). C₁₉H₂₀ ⁷⁹BrN₅O₃ requires 445 231 D66 CH₂

Found 570 (MH⁺). C₂₇H₃₃ ⁷⁹BrFN₇O requires 569. 241 D66 CH₂

Found 454 (MH⁺). C₂₂H₂₄ ⁷⁹BrN₅O requires 453 242 D66 CH₂

Found 448 (MHa⁺). C₂₀H₂₀ ⁷⁹BrN₅O requires 425 243 D66 CH₂

Found 440 (MH⁺). C₂₁H₂₂ ⁷⁹BrN₅O requires 439. 244 D66 CH₂

Found 440 (MH⁺). C₂₁H₂₂ ⁷⁹BrN₅O requires 439. 245 D66 CH₂

Found 443 (MH⁺). C₁₇H₁₇ ⁷⁹Br³⁵Cl₂N₄O requires 442. 246 D66 CH₂

Found 474 (MH⁺). C₂₁H₂₁ ⁷⁹Br³⁵ClN₅O requires 473 259 D80 O

Found 476 (MH⁺). C₂₁H₁₉ ⁷⁹BrFN₃O₂S requires 475. 260 D66 CH₂

Found 454 (MH⁺). C₂₂H₂₄ ⁷⁹BrN₅O requires 453. 261 D66 CH₂

Found 502 (MH⁺). C₂₆H₂₄ ⁷⁹BrN₅O requires 501. 262 D66 CH₂

Found 440 (MH⁺). C₂₁H₂₂ ⁷⁹BrN₅O requires 439. 263 D66 CH₂

Found 504 (MH⁺). C₂₀H₁₉ ⁷⁹Br₂N₅O requires 503 264 D66 CH₂

Found 440 (MH⁺). C₂₁H₂₂BrN₅O requires 439 265 D66 CH₂

Found 504 (MH⁺). C₂₀H₁₉ ⁷⁹Br₂N₅O requires 503. 266 D66 CH₂

Found 544 (MH⁺). C₂₅H₃₁ ⁷⁹BrFN₇O requires 543.

EXAMPLE 93 1-{2-(6,7-Difluoro-quinoxalin-2-ylamino)-methyl]-pyrrolidin-1-yl}-1-[4-(4-fluoro-phenyl)-2-H-pyrazol-3-yl]-methanone

[0299] The amine of D31 (0.085 g) in dimethylformamide (3 ml) was treated with 4-(fluoro-phenyl)-2H-pyrazole-3-carboxylic acid (0.125 g), diisopropylethylamine (0.07 ml) and [O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate] (0.11 g). the mixture was shaken for 48 hours. Solvent was removed at reduced pressure and the residue extracted with dichloromethane. The filtrate was evaporated under reduced pressure and the residue column chromatographed (silica gel, 3% methanol/diethyl ether) to give the title compound (0.1 g).

[0300] Mass Spectrum (API⁺): Found 453 (MH⁺). C₂₃H₁₉F₃N₆O requires 452.

[0301] residue column chromatographed (silica gel, 3% methanolydiethyl ether) to give the title compound (0.1 g).

[0302] Mass Spectrum (API⁺): Found 453 (MH⁺). C₂₃H₁₉F₃N₆O requires 452.

Mass Spectrum (Electrospray Example Amine Ar² Ar¹ LC/MS), API⁺ 94 D31

Found 484 (MH⁺). C₂₄H₂₀F₃N₅OS requires 483 95 D31

Found 467 (MH⁺). C₂₄H₂₁F₃N₆O requires 466 96 D31

Found 468 (MH⁺). C₂₃H₂₀F₃N₇O requires 467 97 D31

Found 394 (MH⁺). C₂₁H₁₇F₂N₅O requires 393 98 D31

Found 419 (MH⁺). C₂₄H₂₀F₂N₄O requires 418 99 D31

Found 478 (MH⁺). C₂₃H₁₉BrF₂N₄O₂requires 477 100 D31

Found 451 (MH⁺). C₂₃H₂₀F₂N₆O₂ 101 D45

Found 484 (MH⁺). C₂₄H₂₀F₃N₅OS requires 483 102 D45

Found 470 (MH⁺). C₂₃H₁₈F₃N₅OS requires 469 103 D45

Found 451 (MH⁺). C₂₃H₂₀F₂N₆O₂requires 450 104 D45

Found 453 (MH⁺). C₂₃H₁₉F₃N₆O requires 452 119 D45

Found 481 (MH⁺). C₂₅H₂₃F₃N₆O requires 480 120 D45

Found 454 (MH⁺). C₂₂H₁₈F₃N₇O requires 453 167 D70

Found 459 (MH⁺). C₂₀H₂₀ ⁷⁹BrFN₆O requires 458 168 D45

Found 470 (MH⁺). C₂₃H₁₈F₃N₅OS requires 469 169 D45

Found 467 (MH⁺). C₂₄H₂₁F₃N₆O requires 466 176 D70

Found 514 (MNa⁺) C₂₀H₁₉ ⁷⁹BrFN₅O₂S requires 491. 177 D70

Found 445 (MH⁺). C₁₉H₁₈ ⁷⁹BrFN₆O requires 444. 178 D70

Found 434 (MH⁺). C₁₉H₁₈ ⁷⁹BrN₅O requires 411. 179 D70

Found 405 (MH⁺). C₁₈H₂₁ ⁷⁹BrN₄O₂requires 404. 180 D70

Found 458 (MH⁺). C₂₀H₂₀ ⁷⁹BrN₅OS requires 457. 181 D70

Found 559 (MH⁺). C₂₅H₃₁ ⁷⁹BrN₆O₂S requires 558. 182 D70

Found 419 (MH⁺). C₁₉H₂₃ ⁷⁹BrN₄O₂requires 418. 183 D70

Found 419 (MH⁺). C₁₉H₂₃ ⁷⁹BrN₄O₂requires 418. 184 D70

Found 467 (MH⁺). C₂₃H₂₃ ⁷⁹BrN₄O₂requires 466. 185 D70

Found 447 (MH⁺). C₂₀H₂₃ ⁷⁹BrN₄O₃requires 446. 186 D70

Found 435 (MH⁺). C₁₉H₂₃ ⁷⁹BrN₄O₃requires 434. 187 D70

Found 419 (MH⁺). C₁₉H₂₃ ⁷⁹BrN₄O₂requires 418 188 D70

Found 455 (MH⁺). C₂₂H₂₃ ⁷⁹BrN₄O₂requires 475 189 D70

Found 476 (MH⁺). C₂₀H₁₉ ⁷⁹BrFN₅OS requires 475. 190 D70

Found 476 (MH⁺). C₂₀H₁₉ ⁷⁹BrFN₅OS requires 475. 191 D70

Found 462 (MH⁺). C₁₉H₁₇ ⁷⁹BrFN₅OS requires 461. 192 D70

Found 444 (MH⁺). C₁₉H₁₈ ⁷⁹BrN₅OS requires 443. 193 D70

Found 458 (MH⁺). C₂₀H₂₀ ⁷⁹BrN₅OS requires 457. 201 D70

Found 462 (MH⁺). C₂₀H₁₇ ⁷⁹BrFN₅OS requires 461. 202 D70

Found 488 (MH⁺). C₂₁H₂₂ ⁷⁹BrN₅O₂S requires 487. 209 D70

Found 505 (MH⁺). C₂₁H₂₂ ⁷⁹BrFN₆OS requires 504 210 D70

Found 459 (MH⁺). C₁₉H₁₉ ⁷⁹BrN₆OS requires 458. 211 D70

Found 488 (MH⁺). C₂₁H₁₉ ⁷⁹BrN₅O₂S requires 487. 212 D70

Found 461 (MH⁺). C₂₀H₁₈ ^(79BrFN) ₄OS requires 460. 213 D70

Found 460 (MH⁺). C₂₁H₂₀ ⁷⁹BrN₅O requires 437. 214 D70

Found 461 (MH⁺). C₁₉H₁₈ ⁷⁹BrFN₆O₂requires 460. 215 D70

Found 473 (MH⁺). C₂₁H₂₁ ⁷⁹BrN₄O₂requires 472. 219 D70

Found 492 (MH⁺). C₂₀H₁₉ ⁷⁹BrFN₅O₂S requires 491. 220 D70

Found 461 (MH⁺). C₁₉H₁₈ ⁷⁹BrFN₆O₂requires 460. 221 D70

Found 443 (MH⁺). C₂₀H₁₉ ⁷⁹BrN₄OS requires 442. 222 D70

Found 462 (MH⁺). C₂₃H₂₀ ⁷⁹BrN₅O requires 461. 223 D70

Found 473 (MH⁺). C₂₁H₂₁ ⁷⁹BrN₄O₂S requires 472. 224 D70

Found 449 (MH⁺). C₁₉H₁₉ ⁷⁹BrN₆O requires 426. 232 D70

Found 516 (MH⁺). C₂₃H₂₇ ⁷⁹BrFN₇O requires 515. 233 D70

Found 490 (MH⁺). C₂₁H₂₁ ⁷⁹BrFN₅OS requires 489. 247 D95

Found 448 (MH⁺). C₂₀H₁₉ ³⁵Cl₂N₅OS requires 447. 248 D93

Found 407 (MH⁺). C₂₁H₂₂N₆O₃ requires 406. 250 D70

Found 440 (MH⁺). C₂₁H₂₂ ⁷⁹BrN₅O requires 439. 251 D95

Found 461 (MH⁺). C₂₁H₂₂ ³⁵ClFN₆OS requires 460. 252 D95

Found 416 (MNa⁺). C₂₁H₂₀ ³⁵ClN₅O requires 393. 253 D95

Found 468 (MNa⁺). C₂₁H₂₁ ³⁵ClFN₅OS requires 445. 254 D95

Found 393 (MH⁺). C₂₂H₂₁ ³⁵ClN₄O requires 392. 255 D70

Found 429 (MH⁺). C₁₆H₁₅ ⁷⁹Br³⁵Cl₂N₄O requires 428 256 D95

Found 520 (MH⁺). C₂₄H₂₇ ³⁵Cl₂N₅O₂S requires 519. 257 D95

Found 427 (MH⁺). C₂₁H₂₃ ³⁵ClN₆O₂requires 426. 258 D70

Found 471 (MH⁺). C₂₁H₂₃ ⁷⁹BrN₆O₂requires 470.

EXAMPLE 105 1-[2-(3-Methyl-[1,2,4]oxadiazol-5-yl)-phenyl]-1-[(S)-2-(oxazolo[4,5-b]]pyridin-2-ylaminomethyl)-piperidin-1-yl]-methanone

[0303] The compound of D41 (0.51 g) and 2-methylsulfanyl-oxazolo[4,5-b]pyridine (0.25 g) were combined and heated under argon at 90° C. for 18 hours The mixture was column chromatographed (5% methanol, diethyl ether eluant) to give the title compound (0.26 g)

[0304] Mass Spectrum (API⁺): Found 419 (MH⁺). C₂₂H₂₂N₆O₃ requires 418.

EXAMPLE 106 1-[2-(3-Methyl-[1,2,4]oxadiazol-5-yl)-phenyl]-{(R)-2-[(methyl-oxazolo[4,5b]pyridin-2-yl-amino)-methyl]piperidin-1-yl}-methanone

[0305] The title compound (0.015 g) was prepared from the compound of D43 (0.15 g) according to the method of Example 105.

[0306] Mass Spectrum (API⁺): Found 433 (MH⁺). C₂₃H₂₄N₆O₃ requires 432.

EXAMPLE 107 6-[((S)-1-{1-[4-(4-Fluoro-phenyl)-1-methyl-1H-pyrazol-3-yl]-methanoyl}-piperidin-2-ylmethyl)-methyl-amino]-nicotinonitrile.

[0307] The title compound (0.078 g) was prepared from the compound of D60 (0.45 g) and 2-chloro-5-cyanopyridine (0.189 g) according to the method of D26

[0308] Mass Spectrum (API⁺): Found 433 (MH⁺). C₂₄H₂₅FN₆O requires 432.

EXAMPLE 108 1-((S)2-{[(6,7-Difluoro-quinoxalin-2-yl)methyl-amino]-methyl}-piperidin-1-yl)-1-[4-(4-fluoro-phenyl)-1-methyl-1H-pyrazol-3-yl]-methanone

[0309] The title compound (0.031 g) was prepared from the compound of D60 (0.15 g) and 2-chloro-6,7difluoroquinoxaline (0.091 g) according to the method of D26

[0310] Mass Spectrum (API⁺): Found 495 (MH⁺). C₂₆H₂₅F₃N₆O requires 494.

EXAMPLE 171 1-{2-[((S)1-{1-[4-(4-Fluoro-phenyl)-1-methyl-1H-pyrazol-3-yl]-methanoyl}-piperidin-2-ylmethyl)-amino]-pyrimidin-5yl)-ethanone

[0311] A mixture of 1-{(S)-2-[(5-Bromo-pyrimidin-2-ylamino)-methyl]-piperidin-1-yl}-1-[4-(4-fluoro-phenyl)-1-methyl-1H-pyrazol-3-yl]-methanone (0.5 g) and 1-ethoxyvinyl)tributyltin (0.42 ml) tetrakis(triphenylphosphine)palladium[0} (0.06 g) was boiled in dioxane (8 ml) for 16 h. 2N Hydrochloric acid was added, the mixture stirred for 90 min, water was added and the mixture extracted (×3) with ethyl acetate. The combined ethyl acetate extracts were dried, solvent removed at reduced pressure and the residue column chromatographed (silica gel, ethyl acetate→2% methanol ethyl acetate to give the title compound (0.3 g) as a yellow foam.

[0312] Mass Spectrum (API⁺): Found 437 (MH⁺). C₂₃H₂₅FN₆O₂ requires 436.

EXAMPLE 172 1-[4-(4-Fluoro-phenyl)-1-methyl-1H-pyrazol-3-yl]-1-((S)-2-{[5-(1-hydroxy-ethyl)-pyrimidin-2-ylamino]-methyl}-piperidin-1-yl)-methanone

[0313] 1-{2-[((S)-1-{1-[4-(4-Fluoro-phenyl)-1-methyl-1H-pyrazol-3-yl]-methanoyl}-piperidin-2-ylmethyl)-amino]-pyrimidin-5-yl}-ethanone (0.2 g) was dissolved in methanol 20 ml) and sodium borohydride (0.4 g) added. The reaction was stirred overnight, water was added and stirring continued for 30 min. The reaction mixture was extracted with ethyl acetate (×3), the organic extracts combined, dried (MgSO₄) and solvent removed at reduced pressure to give the title compound as a colourless foam.

[0314] Mass Spectrum (API⁺): Found 439 (MH⁺). C₂₃H₂₇FN₆O₂ requires 438.

EXAMPLE 173 2-[((S)-1-{1-[4-(4-Fluoro-phenyl)-1-methyl-1H-pyrazol-3-yl]-methanoyl}-piperidin-2-ylmethyl)-amino]-pyrimidine-5-carbonitrile

[0315] 1-{(S)-2-[(5-Bromo-pyrimidin-2-ylamino)methyl]-piperidin-1-yl}-1-[4-4-fluoro-phenyl)-1-methyl-1H-pyrazol-3-yl]-methanone (0.35 g) in N-methylpyrrolidinone (10 ml) containing copper(I)cyanide (0.13 g) was heated to reflux for 5 h. The reaction mixture was diluted with water, filtered (Kieselguhr) and the filtrate extracted with ethyl acetate. The ethyl acetate phase was washed with water and brine, dried (MgSO4), filtered and solvent removed at reduced pressure. The residue was column chromatographed (silica gel; ethyl acetate:pentane 1:1→ ethyl acetate eluant), the appropriate fractions combined and solvent removed at reduced pressure to give the title compound (0.019 g).

[0316] Mass Spectrum (API⁺): Found 420 (MH⁺). C₂₂H₂₂FN₇O requires 419.

EXAMPLE 174 3-(1-{(S)-2-[(6,7-Difluoro-quinoxalin-2-ylamino)-methyl]-piperidin-1-yl}-methanoyl)-N-methyl-benzamide

[0317] The compound of description 71 (0.10 g) was dissolved in dimethylformamide (5 ml) containing HATU (0.095 g) and diisopropylethylamine (0.131 ul) and stirred for 30 in. Methylamine (1M in tetrahydrofuran, 0.125 ml) was added and stirring continued for 16. The reaction mixture was diluted with diethyl ether, washed with water (×3), saturated brine and dried (MgSO₄). Solvent was removed at reduced pressure and the residue column chromatographed (silica gel; ethyl acetate→10% methanol:ethyl acetate to give the title compound (0.018 g).

[0318] Mass Spectrum (API⁺): Found 440 (MH⁺). C₂₃H₂₃F₂N₅O₂ requires 439.

EXAMPLE 194 1-{(S)-2-[(5-Bromo-pyrimidin-2-ylamino)methyl]-pyrrolidin-1-yl-1-[5-(4-fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanone

[0319] A mixture of the amine of D70 (0.070 g), 5-(4-fluoro-phenyl)-2-methyl-thiazole-4-carboxylic acid (0.065 g), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) (0.042 g) and 1-hydroxybenzotriazole hydrate (0.037 g) in dimethylformamide (2 ml) was stirred at ambient temperature for 18 h, evaporated in vacuo and the residue partitioned between ethyl acetate and water. The organic layer was dried (Na₂SO₄), evaporated and the residue chromatographed on silica gel eluting with a 30% -100% ethyl acetate in pentane gradient to afford the title product (0.083 g) as a white solid. Mass-Spectrum (Electrospray LC/MS), API⁺: Found 476 (MH⁺). C₂₀H₁₉ ⁷⁹FN₅OS requires 475.

EXAMPLE 195 1-{(S)-[(5-Bromo-pyrimidin-2-ylamino)-methyl]-pyrrolidin-1-yl}-1-[2-(3-methyl-[1,2,4]oxadiazol-5-yl)-phenyl]-methanone

[0320] The title compound (0.053 g) was obtained from the amine of D70 (0.070 g) and 2-(3-methyl-[1,2,4]oxadiazol-5-yl)-benzoic acid (0.056 g) using the method of Example 194. Mass Spectrum (Electrospray LC/MS): Found 443 (MH⁺). C₁₉H₁₉ ⁷⁹BrN₆O₂ requires 442.

EXAMPLE 196 1-{(S)-2-[5-Bromo-pyrimidin-2-ylamino)-methyl]-pyrrolidin-1-yl}-1-[5-(4-chloro-phenyl)-2-methyl-thiazol4-yl]-methanone

[0321] The title compound (0.078 g) was obtained from the amine of D70 (0.077 g) and 5-(4-chloro-phenyl)-2-methyl-thiazole-4-carboxylic acid (0.076 g) according to the method of Example 32. Mass spectrum (Electrospray LC/MS), API⁺: Found 492 (MH⁺). C₂₀H₁₉ ⁷⁹Br³⁵CIN₅OS requires 491.

EXAMPLE 197 1-{(S)-2-[(5-Bromo-pyridin-2-ylamino)-methyl]-pyrrolidin-1-yl}-1-[5-(4-fluoro-phenyl)-2-methyl-thiazol4-yl]-methanone

[0322] The title compound (0.135 g) was obtained from the amine of D74 (0.11 g) and 5-(4fluoro-phenyl)-2-methyl-thiazole-4-carboxylic acid (0.12 g) according to the method of Example 32. Mass Spectrum API⁺: Found 475 (MH⁺). C₂₁H₂₀ ⁷⁹BrFN₄OS requires 474.

EXAMPLE 198 1-{(S)-2-[(5-Bromo-pyridin-2-ylamino)-methyl]-pyrrolidin-1-yl}-1-[4-(4-fluoro-phenyl)-1-methyl-1H-pyrazol-3-yl]-methanone

[0323] The title compound (0.10 g) was obtained from the amine of D74 (0.11 g) and 4-(4-fluoro-phenyl)-1-methyl-1H-pyrazole-3 carboxylic acid (0.12 g) according to the method of Example 32. Mass Spectrum API⁺: Found 458 (MH⁺). C₂₁H₂₁ ⁷⁹BrFN₅O requires 457.

EXAMPLE 200 1-{3-[(5-Bromo-pyrimidin-2-ylamino)-methyl]-morpholin-4-yl}-1-[4-(4-fluoro-phenyl)-1-methyl-1H-pyrazol-3-yl]-methanone

[0324] The title compound (0.393 g) was obtained from the compound of D80 (0.3 g) and 4-4-fluorophenyl)-1-methyl-1H-pyrazole-3-carboxylic acid (0.242 g) according to the method of Example 32. Mass Spectrum (API⁺): Found 475 (MH⁺). C₂₀H₂₀ ⁷⁹BrFN₆O₂ requires 474.

EXAMPLE 203 3,5-Difluoro4-[((S)1-1-[5-4-fluorophenyl)-2-methyl-thiazol-4yl]-methanoyl)-piperidin-2-ylmethyl)-amino]-benzonitrile

[0325] The title compound (0.090 g) was obtained from the compound of D82 (0.073 g) and 5-(4-fluorophenyl)-2-methyl-thiazole-4-carboxylic acid (0.069 g) according to the method of Example 32. Mass Spectrum (Electrospray LC/MS): Found 471. C₂₄H₂₁F₃N₄OS requires 470.

EXAMPLE 208 3,5-Difluoro-4-[((S)-1-{1-[5-(4-fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanoyl}-pyrrolidin-2-ylmethyl)-amino]-benzonitrile

[0326] The title compound (0.09 g) was obtained from the compound of D84 and 5-(4-fluoro-phenyl)-2-methyl-thiazolecarboxylic acid (0.095 g) according to the method of Example 32. Mass Spectrum (Electrospray LC/MS): Found 457 (MH⁺). C₂₃H₁₉F₃N₄OS requires 456.

EXAMPLE 216 1-{(S)-2-[(5-Ethyl-pyrimidin-2-ylamino)-methyl]-pyrrolidin-1-yl}-1-[5-(4-fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanone

[0327] The title compound (0.05 g) was obtained from the compound of D86 (0.07 g) and 5-(4-fluoro-phenyl)-2-methyl-thiazole-4-carboxylic acid (0.068 g) according to the method of Example 32. Mass Spectrum (Electrospray LC/MS): Found 426 (MH⁺). C₂₂H₂₄FN₅OS requires 425.

EXAMPLE 217 1((S)-2-{[(5-Bromo-pyrimidin-2-yl)-methyl-amino]-methyl}-pyrrolidin-1-yl)-1-[5-(4-fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanone

[0328] The title compound (0.1g) was obtained from the compound of D91 (0.275 g) and 5-(4-fluoro-phenyl)-2-methyl-thiazole-4-carboxylic acid (0.285 g) according to the method of Example 32. Mass Spectrum (Electrospray LC/MS): Found 490 (MH⁺). C₂₁H₂₁ ⁷⁹FN₅OS requires 489.

EXAMPLE 218 1-((S)-2-([(5-Bromo-pyrimidin-2-yl)-methyl-amino]-methyl}-pyrrolidin-1-yl)-1-[4-(4-fluoro-phenyl)-1-methyl-1H-pyrazol-3-yl]-methanone

[0329] The title compound (0.02 g) was obtained from the compound of D91 (0.275 g) and 4-(4-fluoro-phenyl)-1-methyl-1H-pyrazole-3-carboxylic acid (0.260 g) according to the method of Example 32. Mass Spectrum (Electrospray LC/MS): Found 473 (MH⁺). C₂₁H₂₂ ⁷⁹BrFN₆O requires 472.

EXAMPLE 225 1-{2-[((S)-1-{1-[5-(4-Chloro-phenyl)-2-methyl-thiazol-4-yl]-methanoyl}-pyrrolidin-2-ylmethyl)-amino]-pyrimidin-5-yl}-ethanone

[0330] The title product (0.04 g) was obtained from the compound of D93 (0.133 g) and 5-(4-chloro-phenyl)-2-methyl-thiazole-4-carboxylic acid (0.076 g) using a similar procedure to that described in Example 32. Mass Spectrum (Electrospray LC/MS): Found 456 (MH⁺). C₂₂H₂₂ ³⁵CIN₅O₂S requires 455.

EXAMPLE 226 1-{(S)-2-[(5-Chloro-pyrimidin-2-ylamino)-methyl]-pyrrolidin-1-yl}-1-[5-(4-fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanone

[0331] The title product (0.095 g) was obtained from the amine of D95 (0.064 g) and 5-(4-fluorophenyl)-2-methyl-thiazole-4-carboxylic acid (0.071 g) using the method of Example 32. Mass Spectrum (Electrospray LC/MS): Found 432 (MH⁺). C₂₀H₁₉ ³⁵CIFN₅OS requires 431.

EXAMPLE 227 1-{(S)-2-[(5-Chloro-pyrimidin-2-ylamino)-methyl]-pyrrolidin-1-yl}-1-[2-(3-methyl-[1,2,4]oxadiazol-5-yl)-phenyl]-methanone

[0332] The title compound (0.052 g) was obtained from the amine of D95 (0.064 g) and 2-(3-methyl-[1,2,4]oxadiazol-5-yl)-benzoic acid (0.061 g) according to the method of Example 32. Mass Spectrum (Electrospray LC/MS): Found 399 (MH⁺). C₁₉H₁₉ ³⁵CIN₆O₂ requires 398.

EXAMPLE 228 1-[5-(4-Fluoro-phenyl)-2-methyl-thiazol-4-yl]-1-{(S)-2-[(5-methyl-pyrimidin-2-ylamino)-methyl]-pyrrolidin-1-yl}-methanone

[0333] To the compound of Example 194 (0.36 g) in dimethylformamide was added lithium chloride (0.096 g), tetramethyl tin (0.126 ml) and dichlorobis(triphenylphosphine) palladium (0) (0.035 g) and the resulting mixture heated at 100° C. under argon for 18 h. The reaction was then evaporated, diluted with dichloromethane, filtered and the filtrate washed with water, dried and evaporated. Chromatography of the residue on silica gel, eluting with methanol-dichloromethane mixtures, afforded the title product (0.2 g) as a yellow amorphous solid. Mass Spectrum (API⁺): Found 412 (MH⁺). C₂₁H₂₂FN₅OS requires 411.

EXAMPLE 229 6-[((S)-1-{1-[5-(4Fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanoyl}-pyrrolidin-2-ylmethyl)-amino]-nicotinonitrile

[0334] A mixture of the amine of D97 (0.134 g), 5-(4-fluoro-phenyl)-2-methyl-thiazole-4-carboxylic acid (0.172 g), EDC (0.139 g) and 1-hydroxybenzotriazole (0.01 g) in dichloromethane (8 ml) was stirred at ambient temperature for 7 days. The reaction was washed with saturated aqueous sodium bicarbonate solution, dried and evaporated. Chromatography of the residue on silica gel, eluting with ethyl acetate-hexane mixtures afforded the title product (0.196 g). Mass Spectrum (Electrospray LC/MS): Found 422 (MH⁺). C₂₂H₂₀FN₅OS requires 421.

EXAMPLE 234 1-[5-(4-Fluoro-phenyl)-2-methyl-thiazol-4-yl]-1-{(S)-2-[6-methyl-2-methylsulfanyl-pyrimidin-4-ylamino)-methyl]-pyrrolidin-1-yl}-methanone

[0335] The title product (0.095 g) was obtained from the amine of D101 (0.15 g) and the compound of D98 (0.14 g) using a similar method to that described in D69. Mass Spectrum (Electrospray LC/MS): Found 458 (MH⁺). C₂₂H₂₄FN₅OS₂ requires 457.

EXAMPLE 235 1-[5-(4-Fluoro-phenyl)2-methyl-thiazol-4-yl-1-{[(S)-2-[(2-methylsulfanyl-pyrimidin-4-ylamino)-methyl]-pyrrolidin-1-yl}-methanone

[0336] The title compound (0.05 g) was obtained from the amine of D101 (0.15 g) and 4-chloro-2-methylsulfanyl-pyrimidine (0.076 g) using a similar method to that described in D69. Mass Spectrum (Electrospray LC/MS): Found 444 (MH⁺). C₂₁H₂₂FN₅OS₂ requires 443.

[0337] The following compounds were prepared using methods similar to that described in Examples 234 and 235.

Mass spectrum (Electrospray Example Amine Y Ar² Ar¹ LC/MS), API⁺ 236 D101 Bond

Found 494 (MH⁺). C₂₃H₂₃F₄N₅OS requires 493. 237 D101 Bond

Found 426 (MH⁺). C₂₂H₂₄FN₅OS requires 425. 238 D101 Bond

Found 466 (MH⁺). C₂₁H₁₉F₄N₅OS requires 465.

EXAMPLE 239 1-(3-{[(5-Bromo-pyrimidin-2-yl)-methyl-amino]-methyl}-morpholin-4-yl)-1-[5-(4-fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanone

[0338] The title compound (0.056 g) was obtained from the compound of D105 (0.095 g) and 5-(4-fluorophenyl)-2-methyl-thiazole-4-carboxylic acid (0.10 g) according to the method of Example 32. Mass Spectrum (Electrospray LC/MS): Found 506 (MH⁺). C₂₁H₂₁ ⁷⁹BrFN₅O₂S requires 505.

EXAMPLE 240 1-(3-([(5-Bromo-pyrimidin-2-yl)methyl-amino]-methyl}-morpholin-4-yl)-1-[2-(4fluoro-phenyl)-thiophen-3-yl]-methanone

[0339] To the compound of D105 (0.095 g) in dichloromethane (8 ml) containing triethylamine (0.06 ml) was added 2-(4-fluorophenyl)-thiophene-3-carbonyl chloride (0.084 g). After 72 h at ambient temperature the reaction mixture was washed with brine, dried and evaporated; the residue was chromatographed on silica gel, eluting with ethyl acetate-pentane mixtures to afford the title product (0.093 g). Mass Spectrum (Electrospray LC/MS): Found 491 (MH⁺). C₂₁H₂₀ ⁷⁹BrFN₄O₂S requires 490.

EXAMPLE 249 1-[5-(4Fluoro-phenyl)-2-methyl-thiazol-4-yl]-1-{(S)-2-[(5-trifluoromethyl-pyrimidin-2-ylamino)-methyl]-pyrrolidin-1-yl}-methanone EXAMPLE 249 1-[5-(4-Fluoro phenyl)-2-methyl-thiazol-4-yl]-1-{(S)-2-[(5-trifluoromethyl-pyrimidin-2-ylamino)-methyl]-pyrrolidin-1-yl}-methanone

[0340] To the compound from Example 194 (0.36 g) in dimethylformamide (5 ml) was added potassium trifluoroacetate (0.23 g), copper iodide (0.3 g) and toluene (5 ml) and the resulting mixture heated at reflux under Dean-Stark conditions for 3 h, before refluxing for a further 20 h. The reaction mixture was cooled, poured into water/ether and filtered through kieselguhr. The aqueous layer from the filtrate was extracted with ether, and the combined ether extracts washed with water, dried and evaporated. The aqueous was re-extracted with dichloromethane and the extract evaporated. The combined extracts were chromatographed on silica gel, eluting with methanol-dichloromethane mixtures, to afford the title product (0.001 g). Mass Spectrum (lectrospray LC/MS): Found 466 (MH⁺). C₂₁H₁₉F₄N₅OS requires 465.

[0341] The compounds in the table below were prepared using methods described above

Mass Spectrum (Electrospray Example X R Ar² Ar¹ LC/MS), API⁺ 267 CH₂ H

Found 486 (MH⁺). C₂₄H₂₉ ³⁵ClFN₇O requires 485. 268 CH₂ H

Found 526 (MH⁺). C₂₇H₃₃ ³⁵ClFN₇O requires 525. 269 CH₂ H

Found 540 (MH⁺). C₂₈H₃₅ ³⁵ClFN₇O requires 539. 270 CH₂ Me

Found 440 (MH⁺). C₂₁H₂₂ ⁷⁹BrN₅O requires 439. 271 CH₂ Me

Found 457 (MH⁺). C₁₈H₁₉ ⁷⁹Br³⁵Cl₂N₄O requires 456. 272 CH₂ H

Found 489 (MH⁺). C₂₃H₂₆ ³⁵ClFN₆OS requires 488. 273 CH₂ Me

Found 454 (MH⁺). C₂₂H₂₄ ⁷⁹BrN₅O requires 453. 274 CH₂ Me

Found: 454 (MH⁺). C₂₂H₂₄ ⁷⁹BrN₅O requires 453. 275 CH₂ H

Found 446 (MH⁺). C₂₁H₂₁ ³⁵ClFN₅OS requires 445.

[0342] It is understood that the present invention covers all combinations of particular and preferred groups described herein above.

[0343] Determination of Orexin-1 Receptor Antagonist Activity

[0344] The orexin-1 receptor antagonist activity of the compounds of formula (I) was determined in accordance with the following experimental method.

[0345] Experimental Method

[0346] CHO-DG44 cells expressing the human orexin-1 receptor were grown in cell medium (MEM medium with Earl's salts) containing 2 mM L-Glutamine, 0.4 mg/mL G418 Sulphate from GIBCO BRL and 10% heat inactivated fetal calf serum from Gibco BRL. The cells were seeded at 20,000 cells/100 μl/well into 96-well black clear bottom sterile plates from Costar which had been precoated with 10 μg/well of poly-L-lysine from SIGMA. The seeded plates were incubated overnight at 37° C. in 5% CO₂.

[0347] Agonists were prepared as 1 mM stocks in water:DMSO (1:1). EC50 values (the concentration required to produce 50% maximal response) were estimated using 11× half log unit dilutions (Biomek 2000, Beckman) in Tyrode's buffer containing probenecid (10 mM HEPES with 145 mM NaCl, 10 mM glucose, 2.5 mM KCl, 1.5 mM CaCl₂, 1.2 mM MgCl₂ and 2.5mM probenecid; pH7.4). Antagonists were prepared as 10 mM stocks in DMSO (100%). Antagonist IC50 values (the concentration of compound needed to inhibit 50% of the agonist response) were determined against 3.0 nM human orexin-A using 11× half log unit dilutions in Tyrode's buffer containing 10% DMSO and probenecid.

[0348] On the day of assay 50 μl of cell medium containing probenecid (Sigma) and Fluo3AM (Texas Fluorescence Laboratories) was added (Quadra, Tomtec) to each well to give final concentrations of 2.5 mM and 4 μM, respectively. The 96-well plates were incubated for 60 min at 37° C. in 5% CO2. The loading solution containing dye was then aspirated and cells were washed with 4×150 μl Tyrode's buffer containing probenecid and 0.1% gelatin (Denley Cell Wash). The volume of buffer left in each well was 125 μl. Antagonist or buffer (25 μl) was added (Quadra) the cell plates gently shaken and incubated at 37° C. in 5% CO₂ for 30 minutes. Cell plates were then transferred to the Fluorescent Imaging Plate Reader (FLIPR, Molecular Devices) instrument Prior to drug addition a single image of the cell plate was taken (signal test), to evaluate dye loading consistency. The run protocol used 60 images taken at 1 second intervals followed by a further 24 images at 5 second intervals. Agonists were added (by the FLIPR) after 20 seconds (during continuous reading). From each well peak fluorescence was determined over the whole assay period and the mean of readings 1-19 inclusive was subtracted from this figure. The peak increase in fluorescence was plotted against compound concentration and iteratively curve fitted using a four parameter logistic fit (as described by Bowen and Jerman, TiPS, 1995, 16, 413-417) to generate a concentration effect value. Antagonist Kb values were calculated using the equation:

Kb=IC50/(1+([3/EC50])

[0349] where EC50 was the potency of human orexin-A determined in the assay (in nM terms) and IC50 is expressed in molar terms.

[0350] Compounds of Examples tested according to this method had pKb values in the range 6.7-9.7 at the human cloned orexin-1 receptor.

[0351] The orexin-2 receptor antagonist activity of the compounds of formula (I) was determined in accordance with the following experimental method.

[0352] Experimental Method

[0353] CHO-DG44 cells expressing the human orexin-2 receptor were grown in cell medium (MEM medium with Earl's salts) contaning 2 mM L-Glutamine, 0.4 mg/mL G418 Sulphate from GIBCO BRL and 10% heat inactivated fetal calf serum from Gibco BRL. The cells were seeded at 20,000 cells/100 μl/well into 96-well black clear bottom sterile plates from Costar which had been pre-coated with 10 μg/well of poly-L-lysine from SIGMA. The seeded plates were incubated overnight at 37° C. in 5% CO₂.

[0354] Agonists were prepared as 1 mM stocks in water:DMSO (1:1). EC50 values (the concentration required to produce 50% maximal response) were estimated using 11× half log unit dilutions (Biomek 2000, Beckman) in Tyrode's buffer containing probenecid (10 mn HEPES with 145 mM NaCl, 10 mM glucose, 2.5 mM KCl, 1.5 mM CaCl₂, 1.2 mM MgCl₂ and 2.5mM probenecid; pH7.4). Antagonists were prepared as 10 mM stocks in DMSO (100%). Antagonist IC50 values (the concentration of compound needed to inhibit 50% of the agonist response) were determined against 10.0 nM human orexin-A using 11× half log unit dilutions in Tyrode's buffer containing 10% DMSO and probenecid.

[0355] On the day of assay 50 μl of cell medium containing probenecid (Sigma) and Fluo3AM (Texas Fluorescence Laboratories) was added (Quadra, Tomtec) to each well to give final concentrations of 2.5 mM and 4 μM, respectively. The 96-well plates were incubated for 60 min at 37° C. in 5% CO₂. The loading solution containing dye was then aspirated and cells were washed with 4×150 μl Tyrode's buffer containing probenecid and 0.1% gelatin (Denley Cell Wash). The volume of buffer left in each well was 125 μl. Antagonist or buffer (25 μl) was added (Quadra) the cell plates gently shaken and incubated at 37C. in 5% CO₂ for 30 min. Cell plates were then transferred to the Fluorescent Imaging Plate Reader (FLIPR, Molecular Devices) instrument. Prior to drug addition a single image of the cell plate was taken (signal test), to evaluate dye loading consistency. The run protocol used 60 images taken at 1 second intervals followed by a further 24 images at 5 second intervals. Agonists were added (by the FLIPR) after 20 sec (during continuous reading). From each well, peak fluorescence was determined over the whole assay period and the mean of readings 1-19 inclusive was subtracted from this figure. The peak increase in fluorescence was plotted against compound concentration and iteratively curve fitted using a four parameter logistic fit (as described by Bowen and Jerman, TiPS, 1995, 16, 413-417) to generate a concentration effect value. Antagonist Kb values were calculated using the equation:

Kb=IC50/(1+([3/FC50))

[0356] where EC50 was the potency of human orexin-A determined in the assay (in nM terms) and IC50 is expressed in molar terms. Compounds of Examples tested according to this method had pKb values in the range <6.3-9.1 at the human cloned orexin-2 receptor.

[0357] The application of which this description and claims forms part may be used as a basis for priority in respect of any subsequent application. The claims of such subsequent application maybe directed to any feature or combination of features described herein. They may take the form of product, composition, process, or use claims and may include, by way of example and without limitation the following claims:

1 1 1 35 PRT Homo sapien 1 Glu Pro Leu Pro Asp Cys Cys Arg Gln Lys Thr Cys Ser Cys Arg Leu 1 5 10 15 Tyr Glu Leu Leu His Gly Ala Gly Asn His Ala Ala Gly Ile Leu Thr 20 25 30 Leu Asn His 35 

1. A compound of formula (I):

wherein: Y represents a bond, oxygen, or a group (CH₂)_(n), wherein n represents 1, 2 or 3 m represents 1, 2, or 3; p represents 0 or 1; X is NR, wherein R is H or (C₁₋₄)alkyl; Ar¹ is aryl, or a mono or bicyclic heteroaryl group containing up to 3 heteroatoms selected from N, O and S; any of which may be optionally substituted; Ar² represents phenyl or a 5- or 6-membered heterocyclyl group containing up to 3 heteroatoms selected from N, O and S, wherein the phenyl or heterocyclyl group is substituted by R¹ and further optional substituents; or Ar² represents an optionally substituted bicyclic aromatic or bicyclic heteroaromatic group containing up to 3 heteroatoms selected from N, O and S; R¹ represents hydrogen, optionally substituted(C₁₋₄ )alkoxy, halo, cyano, optionally substituted(C₁₋₆)alkyl, optionally substituted phenyl, or an optionally substituted 5- or 6-membered heterocyclyl group containing up to 4 heteroatoms selected from N, O and S; wherein when Y is a bond Ar² can not be 2-naphthyl; when Ar¹ is aryl p is not 1; or a pharmaceutically acceptable salt thereof
 2. A compound of formula (Ia);

wherein: Y represents a bond, oxygen, or a group (CH₂)_(n), wherein n represents 1, 2 or 3 Ar¹ is a mono or bicyclic heteroaryl group containing up to 3 heteroatoms selected from N, O and S; any of which may be optionally substituted; Ar² represents phenyl or a 5- or 6-membered heterocyclyl group containing up to 3 heteroatoms selected from N, O and S, wherein the phenyl or heterocyclyl group is substituted by R¹ and further optional substituents; or Ar² represents an optionally substituted bicyclic aromatic or bicyclic heteroaromatic group containing up to 3 heteroatoms selected from N, O and S; R¹ represents hydrogen, optionally substituted(C₁₋₄)alkoxy, halo, cyano, optionally substituted(C₁₋₆)alkyl, optionally substituted phenyl, or an optionally substituted 5- or 6-membered heterocyclyl group containing up to 4 heteroatoms selected from N, O and S; wherein when Y is a bond then Ar² can not be 2-naphthyl; or a pharmaceutically acceptable salt thereof.
 3. A compound according to claim 1 or 2 wherein Y is a bond, oxygen or (CH₂)_(n) where n is 1 or
 2. 4. A compound according to any preceding claim wherein Ar² represents an optionally substituted phenyl, pyridyl, thiazolyl, pyrazolyl, benzofuryl, naphthyl, triazolyl, quinoxalinyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzothienyl, benzotriazolyl, benzothiazolyl, indolyl or thienyl.
 5. A compound according to any preceding claim wherein Ar¹ represents an optionally substituted is benzoxazolyl, benzimidazolyl, quinoxalinyl, quinazolinyl, pyrimidinyl, pyridinyl, naphthyridinyl, quinolinyl, pyridopyrimidine, thiazolyl, oxazolylpyridinyl, benzothiazolyl, isoquinolinyl or pyrazinyl.
 6. A compound according to any preceding claim wherein R¹ is selected from trifluoromethoxy, methoxy, ethoxy, halo, cyano or an optionally substituted phenyl, pyridyl, pyrazolyl, pyrimidinyl, or oxadiazolyl group.
 7. A compound of formula (I) as defined in any one of Examples 1 to 275, or a pharmaceutically acceptable salt of any one thereof.
 8. A pharmaceutical composition comprising a compound of formula (I) as defined in any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
 9. A method of treating or preventing diseases or disorders where an antagonist of a human orexin receptor is required, which comprises administering to a subject in need thereof an effective amount of a compound of formula (I) as defined in any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof. 